European Journal of Pharmacology ()

1 Contents lists available at ScienceDirect

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4 European Journal of Pharmacology
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journal homepage: www.elsevier.com/locate/ejphar
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Review
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Cisplatin in cancer therapy: Molecular mechanisms of action
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14 Shaloam Dasari, Paul Bernard Tchounwou n
15 Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD RCMI-Center for Environmental Health, College of Science,
16 Engineering and Technology, Jackson State University, 1400 Lynch Street, Box 18750, Jackson, MS 39217, USA
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19 art ic l e i nf o a b s t r a c t
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21 Article history: Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug.
22 Received 27 March 2014 It has been used for treatment of numerous human cancers including bladder, head and neck, lung,
Received in revised form ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ
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13 July 2014
24 cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with
Accepted 14 July 2014
the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and
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subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous
26 Keywords: undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to
27 Cisplatin infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other
28 Platinum-based drugs
platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used.
29 Mechanisms of action
Furthermore, combination therapies of cisplatin with other drugs have been highly considered to
Cancer treatment
30 overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochem-
31 ical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in
32 combination with other drugs) for the treatment of various human cancers. A special attention is paid to
33 its molecular mechanisms of action, and its undesirable side effects.
34 & 2014 Published by Elsevier B.V.
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38 Contents
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40 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
41 2. Cisplatin and other platinum-containing drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
42 3. Uses of cisplatin for cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Cisplatin and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
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3.2. Cisplatin and ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
44
3.3. Cisplatin and carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
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3.4. Cisplatin and breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
46 3.5. Cisplatin and brain cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
47 4. Combination therapy of cisplatin with other cancer drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
48 4.1. Cisplatin and paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
49 4.2. Cisplatin and tegafur-uracil (UFT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
50 4.3. Cisplatin and doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
51 4.4. Cisplatin and gemcitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
52 4.5. Cisplatin and vitamin D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
53 4.6. Other possible drug combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5. Molecular mechanisms of cisplatin pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
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5.1. Cisplatin-induced oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
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5.2. Cisplatin modulation of calcium signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
56 5.3. Cisplatin-induced cell apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
57 5.4. Cisplatin and protein kinase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
58 5.5. Cisplatin and mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
59 5.6. Cisplatin and jun amino-terminal kinase (JNK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
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62 Corresponding author. Tel.: 1 601 979 0777.
63 E-mail address: paul.b.tchounwou@jsums.edu (P. Bernard Tchounwou).
64 http://dx.doi.org/10.1016/j.ejphar.2014.07.025
65 0014-2999/& 2014 Published by Elsevier B.V.
66

Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
 2 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology ()

1 5.7. Cisplatin and p38 mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2 5.8. Cisplatin and AKT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3 5.9. Cisplatin and signaling for DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4 5.10. p53 and DNA damage response to cisplatin treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.11. Cyclobutanedicarboxylate (c-abl) and DNA damage response to cisplatin treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
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5.12. Cisplatin modulation of gene expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
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5.13. Computational studies of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
7 6. Toxicological effects of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
8 6.1. Hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
9 6.2. Cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
10 6.3. Nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
11 6.4. Other organ toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
12 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
13 Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
14 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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1. Introduction
20 drugs) for the treatment of various human cancers, to examine
21 its molecular mechanisms of action, and to discuss it potential
Cisplatin (CAS no. 15663-27-1, MF-Cl2H6N2Pt; NCF-119875),
22 side effects.
cisplatinum, also called cis-diamminedichloroplatinum(II), is a
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metallic (platinum) coordination compound with a square planar
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geometry. It is a white or deep yellow to yelloworange crystalline
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powder at room temperature. It is slightly soluble in water
26 2. Cisplatin and other platinum-containing drugs
and soluble in dimethylprimanide and N,N-dimethylformamide.
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Cisplatin is stable under normal temperatures and pressures, but
28 Since the early seminal work in the preclinical and clinical
may transform slowly over time to the trans-isomer (IARC, 1981;
29 development of cisplatin, several thousand analogs have been
Akron, 2009). Cisplatin has a molecular weight of 301.1 g/mol, a
30 synthesized and tested for properties that would enhance its
density of 3.74 g/cm3, a melting point of 270 1C, a log Kow of  2.19
31 therapeutic index. About 13 of these analogs have been evaluated
and a water solubility of 2.53 g/L at 25 1C (HSDB 2009).
32 in clinical trials, but only one (carboplatin) has provided denite
Cisplatin was rst synthesized by M. Peyrone in 1844 and its
33 advantage over cisplatin and achieved worldwide approval. Nine
chemical structure was rst elucidated by Alfred Werner in 1893.
34 platinum analogs are currently in clinical trials around the world
However, the compound did not gain scientic investigations until
35 ormaplatin (tetraplatin), oxaliplatin, DWA2114R, enloplatin, loba-
the 1960s when the initial observations of Rosenberg et al. (1965)
36 platin, CI-973 (NK-121), 254-S, JM-216, and liposome-entrapped
at Michigan State University pointed out that certain electrolysis
37 cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum
products of platinum mesh electrodes were capable of inhibiting
38 (II) (LNDDP)] (Weiss and Christian, 1993). Fig. 1 presents the
cell division in Escherichia coli created much interest in the
39 chemical structures of cisplatin and four of its analogs including
possible use of these products in cancer chemotherapy. Since the
40 carboplatin, oxaliplatin, ormaplatin and enloplatin.
identication of cis-dichlorodiammineplatinum (II) (cisplatin, r) as
41 From the molecular perspective, cisplatin represents a perfect
the agent responsible for this activity, considerable interest has
42 example of how a small alteration in chemical structure can signi-
been generated in the use of coordination complexes of platinum,
43 cantly affect biological activity in target cell (Goodsell, 2006). As
palladium, and other noble metals in the treatment of cancer.
44 illustrated in Fig. 2, cisplatin, carboplatin and oxaliplatin are composed
Cisplatin has been especially interesting since it has shown
45 of doubly charged platinum ion surrounded by four ligands, with the
anticancer activity in a variety of tumors including cancers of the
46 amine ligands on the left forming stronger interactions with the
ovaries, testes, and solid tumors of the head and neck. It was
47 platinum ion, and the chloride ligands or carboxylate compounds on
discovered to have cytotoxic properties in the 1960s, and by the
48 the right forming leaving groups allowing the platinum ion to form
end of the 1970s it had earned a place as the key ingredient in the
49 bonds with DNA bases (Goodsell, 2006).
systemic treatment of germ cell cancers. Among many chemother-
50 Carboplatin or Cis diammine (1,1-cyclobutanecarboxylato) pla-
apy drugs that are widely used for cancer, cisplatin is one of the
51 tinum (II) is a chemotherapeutic drug used for cancers of ovaries,
most compelling ones. It was the rst FDA-approved platinum
52 lung, head and neck. In terms of its structure, carboplatin differs
compound for cancer treatment in 1978 (Kelland, 2007). This has
53 from cisplatin in that it has a bidentate dicarboxylate (CBDCA)
led to interest in platinum (II)and other metalcontaining com-
54 ligand in place of the two chloride ligands, which are the leaving
pounds as potential anticancer drugs (Frezza et al., 2010).
55 groups in cisplatin (Figs. 1 and 2). It exhibits lower reactivity
Cisplatin is clinically proven to combat different types of cancers
56 and slower DNA binding kinetics, although it forms the same
including sarcomas, cancers of soft tissue, bones, muscles, and blood
57 reaction products in vitro at equivalent doses with cisplatin. Unlike
58 vessels. Although such cancers have recently received better prog- cisplatin, carboplatin may be susceptible to alternative mechan-
59 nosis and therefore have become less life threatening (Desoize and isms. Some studies show that cisplatin and carboplatin cause
60 Madoulet, 2002), signicant challenges remain with regard to their different morphological changes in MCF-7 cell lines while exerting
61 cure. Also, because of drug resistance and considerable side effects, their cytotoxic behavior (Natarajan et al., 1999). The dimin-
62 combination therapy of cisplatin with other cancer drugs has been ished reactivity limits proteincarboplatin complexes, which are
63 applied as novel therapeutic strategies for many human cancers. In excreted. The lower excretion rate of carboplatin means that more
64 this research, we aim to provide a comprehensive review of the is retained in the body, and hence its effects are longer lasting
65 physicochemical properties of cisplatin and related platinum-based (a retention half-life of 30 h for carboplatin, compared to 1.53.6 h
66 drugs, to discuss its uses (either alone or in combination with other in the case of cisplatin).

Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology () 3

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28 Fig. 1. Chemical structures of selected platinum drugs: A-cisplatin; B-carboplatin; C-oxaliplatin; D-ormaplatin; E-enloplatin (Weiss and Christian, 1993).
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31 Relative to cisplatin, the greatest benet of carboplatin is its
32 reduced side effects, particularly the elimination of nephrotoxic
33 effects. The main drawback of carboplatin is its myelo suppressive
34 effect which causes the blood cell and platelet output of bone
35 marrow in the body to decrease quite dramatically, sometimes as
36 low as 10% of its usual production levels (Canetta et al., 1985).
37 Carboplatin is less potent than cisplatin; depending on the type
38 of cancer, carboplatin may only be 1/8 to 1/45 as effective. The
39 clinical standard of dosage of carboplatin is usually a 4:1 ratio
40 compared to cisplatin; that is, for a dose that usually requires a
41 particular dose of cisplatin, four times more carboplatin is needed
42 to achieve the same effectiveness. The stable property of carbo-
43 platin is a mixed blessing; once uptake of the drug occurs, its
44 retention half-life is considerably longer than cisplatin, but it is
45 also this inertness that causes carboplatin to go right through the
46 human body, and up to 90% of the carboplatin given can be
47 recovered in urine (Go and Adjei, 1999).
48 In order to overcome cisplatin resistance, other platinum (Pt)
49 compounds have been developed and, in the last ten years,
50 Pt-derivatives with reporting activity have also been synthesized.
51 The rst generation of reporting Pt-compounds was based on
52 linking a uorescent molecule (e.g. cyanine) to cisplatin, but more
53 recent studies have focused on strategies to synthesize intrinsi-
54 cally uorescent derivatives. Accordingly, bile acid platinum com-
55 pounds have shown uorescence intensity that is stable at room
56 temperature for a long time; this uorescence is maintained after
57 binding to oligonucleotides or DNA. Because of this, the binding
58 mode of these compounds to DNA can be easily analyzed both by
59 ow injection and uorescence techniques, showing that although
60 these compounds target the nuclei, they form adduct with the
61 DNA that are different from those due to cisplatin. In line with this,
62 Fig. 2. Computational molecular structures of cisplatin, carboplatin and oxalipla- these bile acid derivatives have shown increased cytotoxicity and
63 tion. These platinum compounds are composed of doubly charged platinum ion ability to overcome resistance as compared to cisplatin in several
surrounded by four ligands; with the amine ligands on the left forming stronger
64 interactions with the platinum ion, and the chloride ligands or carboxylate
cell lines. Moreover, in contrast to cisplatin, the activity of these
65 compounds on the right forming leaving groups allowing the platinum ion to form compounds does not seem to be restricted to cycling cells but they
66 bonds with DNA bases (Goodsell, 2006). also seem to kill resting cells (Rodriguez-Fernandez et al., 2009)

Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
 4 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology ()

1 3. Uses of cisplatin for cancer treatment survival rate of approximately 50% has not changed over the last
2 decades. Cisplatin alone is not an effective drug in treating the
3 3.1. Cisplatin and lung cancer disease. A randomized comparison of cisplatin alone or in combi-
4 nation with methotrexate, vinblastine, doxorubicin, and or gemci-
5 Lung cancer remains one of the most common types of fatal tabine in patients with metastatic urothelial carcinoma has been
6 malignancies (Youlden et al., 2008). Small cell lung cancers (SCLCs) reported (Scher, 1992; Matsuki et al., 2013).
7 represent 15% of all lung cancers (Chen et al., 2009). At present,
8 platinum based treatments are key drugs for SCLC (Abrams et al., 3.4. Cisplatin and breast cancer
9 2003). Cisplatin and carboplatin are two of the most common
10 types of platinum based treatments used in SCLC chemotherapy Breast cancer is one of the leading causes of women mortality
11 (Go and Adjei, 1999). In clinical trials, cisplatin is often selected worldwide. Chemotherapy is the only option for treating the
12 due to its strong antitumor activity, but its adverse effects include malignant breast cancer and condition for increases the lifespan
13 renal toxicity (Iwasaki et al., 2005), nausea and vomiting (Kosmas of the patient (Decatris et al., 2004). Chemotherapeutic agents
14 et al., 2001). Therefore, to avoid renal toxicity, urine volumes have been developed to counter the continuing breast cancer
15 should be monitored and large-dose infusion is mandatory in problem. However, most chemotherapeutic drugs effectively tar-
16 cisplatin based chemotherapy. In clinical practice, carboplatin has get rapidly dividing cells causing damage and are thus referred to
17 been considered to be a substitute for cisplatin without any as cytotoxic drugs. Cisplatin is an important chemotherapeutic
18 apparent loss of therapeutic efcacy since aggressive hydration is agent used widely or the treatment of a variety of malignancies,
19 often problematic. including breast, testicular, ovarian, cervical, prostate, head and
20 The standard of care for localized non-small-cell lung cancer neck, bladder, lung and refractory non-Hodgkin's lymphomas
21 (NSCLC) is surgery followed by, in case of stage II and III disease, (Tsimberidou et al., 2009; Dhar et al., 2011). The cytotoxic effect
22 adjuvant cisplatin-based chemotherapy. The Lung Adjuvant is likely a result of inhibition of replication by cisplatin-DNA
23 Cisplatin Evaluation program, a pooled analysis of the ve largest adducts and induction of apoptosis (Siddik, 2003).
24 trials, recently showed an absolute 5-year survival benet of 5.3%
25 with adjuvant chemotherapy as well as the NSCLC meta-analysis 3.5. Cisplatin and brain cancer
26 (Pignon et al., 2008).
27 CD133, a surface glycoprotein linked to organ-specic stem Glioblastomamultiforme (GBM) is the most common primary
28 cells, has been described as a marker of cancer-initiating cells in malignant brain tumor, and with rare exception, is invariably fatal
29 different tumor types. It has also been reported that a CD133 , (Stupp et al., 2005). The current standard of care for patients
30 epithelial-specic antigen-positive (CD133 ESA ) population is with GBMs consists of surgery and radiotherapy in combination
31 increased in primary non-small cell lung cancer (NSCLC) compared with temozolomide, followed by repetitive cycles of temozolo-
32 with normal lung tissue (Bertolini et al., 2009). mide (Stupp et al., 2009). Although the survival advantage of
33 this combined treatment regimen was still evident at 5 years, the
34 3.2. Cisplatin and ovarian cancer increase in overall median survival was only for 2.5 months.
35 Cisplatin therapy is also used for recurrent childhood brain
36 Ovarian cancer has the highest mortality among gynecologic tumors(Khan et al., 1982),as well as in other cancers such as
37 cancers. Most patients with ovarian cancer are diagnosed at late gastric cancer (Koizumi et al., 2008), anal cancer (Ajani et al.,
38 stages due to lack of effective screening strategies and specic 2008), and leukemia (Previati et al., 2006).
39 symptoms associated with early-stage disease. Conventional treat-
40 ment for late stages of ovarian cancers is surgical excision followed
41 by platinum/taxane combination chemotherapy. Although this 4. Combination therapy of cisplatin with other cancer drugs
42 treatment regime is effective as the rst-line treatment, recur-
43 rence occurs in up to 75% of ovarian cancer patients. Patients Cisplatin combination chemotherapy is the basis of treatment
44 with recurrent ovarian cancer ultimately develop resistance to of many cancers. Platinum responsiveness is high primarily
45 chemotherapy and eventually succumb to the disease (Agarwal but many cancer patients will ultimately relapse with cisplatin-
46 and Kaye, 2003). About 90% of ovarian cancers arise originally resistant disease. Hence, drug resistance has been observed in
47 from ovaries with an unknown reason, while the remainder has many patients who have relapsed from cisplatin treatment. The
48 hereditary background, or are associated with breast and colon proposed mechanisms of cisplatin resistance include changes in
49 cancers (Lynch et al., 2009). Cisplatin derivatives are used as the cellular uptake and efux of cisplatin, increased biotransformation
50 mainline treatment of ovarian cancer, despite their severe side and detoxication in the liver, and increase in DNA repair and anti-
51 effects and development of resistance. Cisplatin is used in combi- apoptotic mechanisms (Gottesman et al., 2002). To overcome
52 nation with other chemical agents or compounds to treat ovarian resistance, cisplatin is commonly used in combination with some
53 cancer in both the resistant and sensitive cell lines. For example other drugs in treating ovarian cancer, biliary tract cancer, lung
54 cisplatin is used along with honey venom (Alizadehnohi et al., cancer (diffuse malignant pleural mesothelioma), gastric cancer,
55 2012), withaferin (Kakar et al., 2012), trichostatin A or 5-aza-20 - carcinoma of salivary gland origin, breast, colon, lung, prostate,
56 deoxycytidine (Meng et al., 2013), overcoming chemotherapy melanoma and pancreatic cancer cell lines, squamous cell carci-
57 resistance of ovarian cancer cells by liposomal cisplatin (Koch noma of male genitial tract, urothelial bladder cancer, and cervical
58 et al., 2013) cancer. Table 1 presents a synopsis of cisplatin combination
59 therapy with other cancer drugs and targeted cancers.
60 3.3. Cisplatin and carcinoma
61 4.1. Cisplatin and paclitaxel
62 Head and neck squamous cell carcinoma (HNSCC) is a common
63 malignant disease with more than 600,000 new cases registered Paclitaxel is a mitotic agent that binds preferentially to micro-
64 worldwide every year (Parkin et al., 2005). Despite improved tubules (Parness et al., 1981) and the resulting stabilization
65 treatment options, including surgery, radiation and chemotherapy, of microtubules inhibits the reorganization of the microtubule
66 HNSCC is associated with a high mortality rate. The overall 5-year network. Paclitaxel has been demonstrated to be active against

Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
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 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology () 5

1 Table 1
2 Combination therapy of cisplatin and other cancer drugs.
3
Combination drug(s) Cancer type Reference(s)
4
5 Paclitaxel Ovarian carcinoma, breast carcinoma, lung carcinoma, Sarosy, Kohn et al. (1992),McGuire et al. (1989),
6 melanoma, head and neck carcinoma Einzig et al. (1992),Holmes et al. (1991),
7 Murphy et al. (1993),
Legha et al. (1990), Einzig et al. (1991), Forastiere (1994)
8 Paclitaxel and 5-FU Gastric and esophagogastric adenocarcinoma Kim et al. (1999)
9 UFT Non small lung carcinoma Ichinose et al. (2000)
10 Doxorubicin Diffuse malignant pleural mesothelioma Ardizzoni et al. (1991)
11 Cyclophosphamide and doxorubicin Salivary gland advanced carcinoma Dreyfuss et al. (1987)
Gemcitabine Biliary cancer Valle et al. (2010)
12
Osthole Lung cancer Xu et al. (2013)
13 Honeybee venom Ovarian cancer Alizadehnohi et al. (2012)
14 Anvirzel Breast, colon, lung, prostate, melanoma and pancreatic Apostolou et al. (2013)
15 cancer
16 Bevacizumab Non small lung carcinoma Du et al. (2013)
Vinbalstine and bleomycin Metastatic granulosa cell tumors in ovary Colombo et al. (1986)
17 Methotrexate and bleomycin Advanced squamous cell carcinoma of the male Dexeus et al. (1991)
18 genital tract
19 Everolimus Urothelial bladder cancer Pinto-Leite, et al. (2013)
20 Fluorouracil, doxorubicin and Salivary gland carcinoma Dimery et al. (1990)
cyclophosphamide
21
Metformin Lung adenocarcinoma Lin et al. (2013)
22 Oxaliplatin, quercetin and thymoquinone Ovarian cancer Nessa et al. (2011)
23 Olaparib PTEN decient lung cancer Minami et al. (2013)
24 Tetra arsenic oxide Cervical cancer Byun et al. (2013)
25 Vindesine Non small lung carcinoma Le et al. (1994)
-galactosyl-pyrrolidinyldiazeniumdiolate Glial cells of brain Human cervical cancer Deng et al. (2013)
26 Gliosarcoma cell lines
27
28
29 previously treated ovarian carcinoma (Sarosy et al., 1992; McGuire 4.5. Cisplatin and vitamin D
30 et al., 1989; Einzig et al., 1992), breast carcinoma (Holmes et al.,
31 1991), lung carcinoma (Murphy et al., 1993), and melanoma (Legha Vitamin D and its analogs regulate gene expression by binding
32 et al., 1990; Einzig et al., 1991) as well as for head and neck to specic vitamin D receptors (VDR). Upon ligand activation and
33 carcinoma (Forastiere, 1994). The combination chemotherapy with dimerization with retinoid X receptor (RXR), VDRRXR hetero-
34 paclitaxel, cisplatin and uorouracil is an active and tolerable as dimers bind specic nucleotide sequences, vitamin D response
35 rst-line and second line therapies in Chinese patients with elements (VDREs), in target genes to activate or repress their
36 advanced gastric and esophagogastric junction adenocarcinoma expression (Baniahmad and Tsai, 1993). A number of vitamin D
37 which showed a better tolerance has also been reported (Kim et target genes have been identied in several tumor cell types: p21,
38 al., 1999) E-cadherin, c-Jun N-terminal kinase (JNK), c-Myc oncogene,
39 insulin-like transforming growth factor family and their receptors
40 (Saramaki et al., 2006; Nagpal et al., 2005).
41 4.2. Cisplatin and tegafur-uracil (UFT) Cisplatin is used along with vitamin D in treating squamous cell
42 carcinoma (Light et al., 1997) and colon cancer (Milczarek et al.,
43 UFT is an oral anticancer agent comprised of tegafur and uracil 2013). Published research has shown that pre-treatment for 72 h
44 in a 1:4 xed molar ratio and is absorbed very well from the small of human promyelocytic leukemia (HL-60) cells with calcitriol or
45 intestine (Fujii et al., 1979). Combination chemotherapy comprised its new analogs signicantly potentiated their sensitivity to the
46 of oral UFT (a combination of tegafur and uracil) and cisplatin was antiproliferative effect in vitro of cisplatin, doxorubicin or genis-
47 shown to be an effective regimen for the treatment of advanced tein. Moreover, for all cytotoxic agents tested a synergistic anti-
48 non-small cell lung carcinoma (Ichinose et al., 2000). proliferative effect was observed. This effect was expressed as a
49 signicant decrease of the ID50 (inhibitory dose 50%) values for
50 4.3. Cisplatin and doxorubicin each cytotoxic agent applied after pretreatment of HL-60 cells
51 with calcitriol or its analogs in comparison with the effect of
52 The combination of doxorubicin and cisplatin is effective and cytotoxic agent applied alone (Siwinska et al., 2001).
53 well tolerated. It might be considered for palliation of symptomatic
54 patients with diffuse malignant pleural mesothelioma DMPM
55 (Ardizzoni et al., 1991). Cyclophosphamide, doxorubicin, and cispla- 4.6. Other possible drug combinations
56 tin combination chemotherapy for advanced carcinomas of salivary
57 gland origin showed encouraging results (Dreyfuss et al., 1987). Cisplatin is also used in combination with natural compounds
58 like osthole in lung cancer cell lines (Xu et al., 2013), honey bee
59 venom in ovarian cancer cells (Alizadehnohi et al., 2012), anvirzel
60 4.4. Cisplatin and gemcitabine in breast, colon, lung, prostate, melanoma and pancreatic cancer
61 cell lines (Apostolou et al., 2013), bevacizumab in non-small cell
62 As compared with gemcitabine alone, cisplatin plus gemcita- lung cancer mediated malignant pleural effusion (Du et al., 2013),
63 bine was associated with a signicant survival advantage without vinblastine and bleomycin in metastatic granulosa cell tumor of
64 the addition of substantial toxicity. Cisplatin plus gemcitabine is an the ovary (Colombo et al., 1986), methotrexate, bleomycin and
65 appropriate option for the treatment of patients with advanced cisplatin for advanced squamous cell carcinoma of the male genital
66 biliary cancer (Valle et al., 2010). tract (Dexeus et al., 1991).

Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
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 6 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology ()
1 Everolimus combined with cisplatin has a potential role in
2 treatment of urothelial bladder cancer (Pinto-Leite et al., 2013),
3 Fluorouracil, doxorubicin, cyclophosphamide, and cisplatin com-
4 bination chemotherapy has been used in advanced or recurrent
5 salivary gland carcinoma (Dimery et al., 1990). Metformin has been
6 shown to enhance cisplatin cytotoxicity by suppressing Stat3
7 activity independently of the LKB1-AMPK pathway (Lin et al.,
8 2013).
9 Synergistic interactions have been reported for -galacto-
10 syl-pyrrolidinyldiazeniumdiolate and cisplatin combination
11 chemotherapy against glial cells of brain, human cervical and
12 gliosarcoma cell lines (Deng et al., 2013). Cisplatin and oxaliplatin
13 in combination with quercetin and thymoquinone in human
14 ovarian tumour models is the best combination to treat ovarian
15 cancer (Nessa et al., 2011). Olaparib in combination with cisplatin
16 has a synergistic effect on PTEN-Decient lung cancer Cells
17 (Minami et al., 2013). Tetraarsenic oxide and cisplatin induce
18 apoptotic synergism in cervical cancer (Byun et al., 2013). Vinde-
19 sine and cisplatin combination chemotherapy compared with
20 vindesine as a single agent in the management of non-small cell
21 lung cancer seemed to be more effective (Le et al., 1994).
22 In ovarian carcinoma treatment, the combination of cisplatin
23 and paclitaxel produced a more encouraging response rate (73%)
24 (McGuire et al., 1996). A single institutional Phase II trial using
25 cisplatin and oral UFT administration in place of protracted
26 intravenous injection of 5-FU yielded a 35% response rate and a
27 median survival time of 11 months in 31 patients with advanced
28 Q3 NSCLC (Ichinose, Takanashi et al., 1995). The addition of cisplatin to
29 cyclophosphamide and doxorubicin (CAP) has been recently asso-
30 ciated with overall response rates of 5700% and complete
31 response rates of 2675% in small series of patients (Creagan et
32 al., 1983; Alberts et al., 1981; Eisenberger, 1985). Cisplatin is known
33 to have an additive or synergistic effect in combination with
34 gemcitabine in a number of different tumor types (Crino et al.,
35 1997; von der et al., 2005; Hitt et al., 1998).
36 Photodynamic therapy (PDT), which is the administration of a
37 photosensitiser followed by visible light activation, is a promising
38 route to avoid damage to healthy cells and the surrounding tissue.
39 Transition metal complexes as photochemotherapeutic agents are
40 an attractive option for further development in the eld of
41 photoactivated chemotherapy (PACT). These complexes exhibit
42 different numbers and types of excited states which are easily
43 accessible upon light irradiation, subsequently giving rise to the
44 formation of various photoproducts that can enable a distinct
45 mode of action. Platinumdiazido complexes are promising can-
46 didates for PACT due to the low cytotoxicity when irradiated with
47 visible light (Shaili, 2014).
48 Cisplatin resistance is correlated with autophagy induction in
49 a panel of ovarian cancer cells (Wang and Wu, 2014). Previous
50 studies demonstrated that A549/CDDP cells acquired an epithelial-
51 mesenchymal transition (EMT) phenotype, with morphological
52 changes including acquisition of a spindle-like broblastic pheno-
53 type, downregulation of E-cadherin, upregulation of mesenchymal
54 markers (vimentin, Snail and Slug), and increased capability of
55 invasion and migration in case of human lung cancer cell lines.
56 (Demonstrated that A549/CDDP cells acquired an epithelial-
57 mesenchymal transition (EMT) phenotype, with morphological
58 changes including acquisition of a spindle-like broblastic pheno-
59 type, downregulation of E-cadherin, upregulation of mesenchymal
60 markers (vimentin, Snail and Slug), and increased capability of
61 invasion and migration in case of human lung cancer cell lines
62 (Wang et al., 2014).
63 It has been hypothesized that Rac1, a Rho GTPase, is implicated
64 in HNSCC insensitivity to chemo-radiotherapy resulting in tumour
65 recurrence development in head and neck squamous cell carci-
66 noma (Skvortsov et al., 2014). Cisplatin resistance in colorectal
Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
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cancer is due to adaptive activation of Nrf2 may contribute to the
development of acquired drug-resistance (Chian et al., 2014). It is
also indicated that AQP5 is associated with drug resistance of
colon cancer (Shi et al., 2014). In chondrosarcoma cells over-
expression of EGFR contributed to cisplatin resistance (Song et
al., 2014). Due to loss of homeodomain-interacting protein kinase-
2 (HIPK2) contributes to cell proliferation and tumorigenesis in
bladder cancer (Lin et al., 2014).
5. Molecular mechanisms of cisplatin pharmacology
Several membrane transporters of platinum compounds analo-
gous to MDR1 including the efux ATPases (MRPs, ATP7A/B), and
the solute carrier importers (CTR1, the SLCs, AQP2, and AQP9),
have been reported. MDR1 is an ATP-binding cassette transporter
known for years as P-glycoprotein (Shen et al , 2012; Johnson et al.,
1996). The uptake of cisplatin is mediated by the copper trans-
porter Ctr1 in yeast and mammals (Ishida et al., 2002). It has been
further conrmed in human cells that cisplatin triggers rapid
degradation of the copper membrane transporter CTR1, with
diminished inux of cisplatin, resulting in resistance to the drug
(Lin et al., 2002; Holzer et al., 2006). Genetic knockout of CTR1
results in cellular resistance to cisplatin in vivo. Cells with
increased CTR1 expression exhibit increased platinum accumula-
tion and, in most instances, increased sensitivity to cisplatin.
TMEM205, a membrane protein has been associated with cellular
resistance to cisplatin was identied. Analysis of TMEM205
expression proles in normal human tissues indicates a differen-
tial expression pattern with higher expression levels in the liver,
pancreas, and adrenal glands. So, overexpression of TMEM205 in
CP-r cells may play a role in cellular resistance to platinum and
would also be valuable as a biomarker or target in cancer
chemotherapy (Shen et al., 2012). Glucose Transporter 1 (Glut1)
is not proposed to directly transport cisplatin, the mislocalization
of the transporter exacerbates the cisplatin resistance phenotype
(Shen et al., 2012).
Cisplatin becomes activated once it enters the cell. In the
cytoplasm the chloride atoms on cisplatin are displaced by water
molecules. This hydrolyzed product is a potent electrophile that
can react with any nucleophile, including the sulfhydryl groups on
proteins and nitrogen donor atoms on nucleic acids. Cisplatin
binds to the N7 reactive center on purine residues and as such can
cause deoxyribonucleic acid (DNA) damage in cancer cells, block-
ing cell division and resulting in apoptotic cell death. The 1,2-
intrastrand cross-links of purine bases with cisplatin are the most
notable among the changes in DNA. These include the 1,2-
intrastrand d(GpG) adducts 1,2-intrastrand d(ApG) adducts repre-
senting about 90% and 10% of adducts, respectively. 1,3-intrastrand
d(GpXpG) adducts and other adducts such as inter-strand cross-
links and nonfunctional adducts have been reported to contribute
to cisplatin's toxicity. Hence, published research from many
laboratories has implicated DNA as a critical target for cisplatin
cytotoxicity, the most revealing evidence being the hypersensitiv-
ity to cisplatin by both prokaryotic and eukaryotic cells decient in
DNA repair (Beck and Brubaker, 1973; Fraval et al., 1978). As
illustrated in Fig. 3, several molecular mechanisms leading to
apoptosis have been implicated in cisplatin treatment of human
cancers.
5.1. Cisplatin-induced oxidative stress
Under normal physiological conditions, cells control reactive oxy-
gen species levels by balancing the generation of reactive oxygen
species with their elimination by scavenging system (reduced
 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology () 7

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42 Fig. 3. Overview of molecular mechanisms of cisplatin in cancer treatment.

43
44 glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT). But Excessive reactive oxygen species can induce apoptosis through
45 under oxidative stress conditions, excessive reactive oxygen species both the extrinsic and intrinsic pathways (Ozben, 2007). In the
46 can damage cellular proteins, lipids and DNA, leading to fatal lesions in extrinsic pathway of apoptosis, reactive oxygen species are gener-
47 cells that contribute to carcinogenesis. Cancer cells exhibit greater ated by Fas ligand as an upstream event for Fas activation via
48 reactive oxygen species stress than normal cells do, partly due to phosphorylation, which is necessary for subsequent recruitment of
49 oncogenic stimulation, increased metabolic activity and mitochondrial Fas-associated protein with death domain and caspase 8 as well as
50 malfunction. Oxidative stress is the one of most important mechan- apoptosis induction (Gupta et al., 2012). In the intrinsic pathway,
51 isms involved in cisplatin toxicity. The mitochondrion is the primary reactive oxygen species function to facilitate cytochrome c release
52 target for cisplatin induced oxidative stress, resulting in loss of by activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well as
53 mitochondrial protein sulfhydrl group, calcium uptake inhibition and inhibiting pore-destabilizing proteins (Bcl-2-associated X protein,
54 reduction of mitochondrial membrane potential (Saad et al., 2004) Bcl-2 homologous antagonist/killer) (Martindale and Holbrook,
55 Exposure to oxidative stress can upset regular biological func- 2002). An even higher reactive oxygen species level can result in
56 tions. Cisplatin also induces reactive oxygen species that trigger both apoptosis and necrosis in cancer cells (Hampton and
57 cell death besides DNA damage. Cell death occurs upon immediate Orrenius, 1997). Reactive oxygen species can also induce cell death
58 activation of numerous signaling pathways, whereas the denite through autophagy, which is a self-catabolic process involving
59 pathways depend on the (cancer) cell. The formation of reactive sequestration of cytoplasmic contents (exhausted organelles and
60 oxygen species depends on the concentration of cis-diamminedi- protein aggregates), for degradation in lyposomes (Shrivastava
61 chloro platinum(II) and the length of exposure (Brozovic et al., et al., 2011)
62 2010). The intracellular redox homeostasis is maintained by the
63 thiol group (SH) containing molecules. Under certain conditions a 5.2. Cisplatin modulation of calcium signaling
64 thiol group may lead to formation of thiyl radicals that in turn can
65 interact with molecular oxygen, therefore generating reactive Cisplatin, under low intracellular chloride ion concentrations,
66 oxygen species (Desoize, 2002). has been shown to hydrolyze into variously charged reactive

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 8 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology ()
1 species including monoaqua [cis-(NH)PtCI(HO)] and diaquated
2 [cis-(NH)Pt(HO)]2 forms (Jennerwein and Andrews, 1995;
3 Aggarwal et al., 1980). These hydrolyzed forms of cisplatin have
4 been shown to be 1000 times more reactive than normal cisplatin,
5 and act through the inhibition of mitochondrial respiration by
6 uncoupling oxidative phosphorylation (Aggarwal, 1993). This
7 result in an efux of calcium from the mitochondria and a
8 temporary increase in the cellular calcium levels, which is thought
9 to play a signicant role in the disruption of normal calcium
10 homeostasis, and hence cell function.
11 Mitochondrial glutathione (GSH) seems to be essential in the
12 regulation of inner mitochondrial permeability and enzyme func-
13 tion by keeping SH in the reduced state. When the SH-groups of
14 enzymes are not maintained in a reduced form, they become
15 inactivated. Cisplatin induced toxicities, especially nephrotoxicity,
16 seem to be related to a decrease in the intracellular concentrations
17 of GSH and protein bound SH-groups. Nicotinamide adenine
18 dinucleotide (NADH), which helps to maintain SH groups, declines
19 with cisplatin treatment. Consequently, this depletion of GSH and
20 NADH appears to result in the inhibition of some dehydrogenases,
21 resulting in the uncoupling of oxidative phosphorylation leading
22 to hydroxyl radical formation and oxidative stress. These free
23 radicals attack polyunsaturated lipids and proteins and initiate
24 lipid per oxidation. This process becomes autolytic and causes
25 severe damage to membrane integrity (Aggarwal, 1998).
26 In summary, cisplatin's disruption of calcium homeostasis
27 initiates primary events such as lipid per oxidation and enzyme
28 inhibition. These events damage the cells through mitochondrial
29 damage, inhibition of mitochondrial function, depletion of adeno-
30 sine triphosphate (ATP) and other cofactors. This probably leads to
31 apoptosis and tissue necrosis. Thus, it seems that elevated calcium
32 levels, via calcium supplementation, may act as another means of
33 cytoprotection, by competing for binding sites with cisplatin and
34 prevent various toxicities associated with it.
35
36 5.3. Cisplatin-induced cell apoptosis
37
38 Apoptosis is a controlled type of cell death which is energy-
39 dependent leading to cell shrinkage, chromatin condensation,
40 membrane budding, phosphatidylserine externalization, and acti-
41 vation of a family of cysteine proteases called caspases (Salvesen
42 and Dixit, 1997; Cummings et al., 2000). Caspase activation is the
43 key step in the beginning of apoptosis, and several stimuli activate
44 caspases, including those that activate plasma membrane death
45 receptors (caspase 8) and cause mitochondrial dysfunction (cas-
46 pase 9). Caspases are either initiators or executioners of apoptosis.
47 Initiator caspases include caspases 8 and 9, and activation of these
48 caspases results in activation of downstream or executioner
49 caspases such as caspases 3 and 7 (Salvesen and Abrams, 2004).
50 Executioner caspases are accountable for many of the biochemical
51 characteristics of apoptosis, including cleavage and activation of
52 poly (ADP-ribose) polymerase and of the inhibitor of caspase
53 activator domain protein, which leads to DNA fragmentation.
54 Cisplatin primarily induces cell death by apoptosis and a defect
55 in apoptotic signaling could also confer cisplatin resistance. There
56 are two major pathways of apoptotic cell death (Nunez et al., 1998;
57 Kischkel et al., 1995). The extrinsic pathway is initiated when
58 ligands bind to the tumor necrosis factor- (TNF) receptor super
59 family followed by oligomerization and recruitment of procaspase-
60 8 via adapter molecules to form the death-inducing signaling
61 complex (DISC). The intrinsic pathway is initiated by cellular
62 stress, such as DNA damage, resulting in release of cytochrome-c
63 from the mitochondria causing activation of procaspase-9 through
64 the interaction with apoptosis promoting activating factor-1
65 (APAF-1) and formation of an active apoptosome complex. Bcl-2
66 family proteins regulate DNA damage-induced apoptosis by
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regulating the release of mitochondrial cytochrome c in response
to DNA damage. Cisplatin-induced genotoxic stress activates
multiple signal transduction pathways, which can contribute to
apoptosis or chemo resistance.
5.4. Cisplatin and protein kinase C
Protein kinase C [PKC] is a family closely related phospholipid
dependent enzymes that play critical roles in signal transduction
and cell regulation (Basu and Sivaprasad, 2007; Newton, 2003;
Basu, 1993; Nishizuka, 1992). There have been contrasting on
reports whether activation or down regulation of PKC is necessary
for cisplatin sensitization (Isonishi et al., 1990; Hirata et al., 1993).
The effects of PKC on cellular sensitivity/resistance to cisplatin
depend on the pattern of the PKC isozymes as well as on the
cellular context (Basu and Krishnamurthy, 2010).
5.5. Cisplatin and mitogen-activated protein kinase (MAPK)
Mitogen activated protein kinases are a family of structurally
related serine/threonine protein kinases that coordinate various
extra cellular signals to regulate cell growth and survival (Chang
and Karin, 2001; Johnson and Lapadat, 2002; Marshall, 1995).
Cisplatin has been shown to cause activation of ERK in several cell
types although there are controversies whether activation of ERK
prevents or contributes to cisplatin induced cell death (Tang et al.,
2010; Wang et al., 2000; Yeh et al., 2002; Nowak, 2002; Hayakawa
et al., 1999; Persons et al., 1999; Basu and Tu, 2005). Cisplatin-
induced extracellular-signal-regulated kinase (ERK) activation pre-
cedes p53-mediated DNA damage response since ERK directly
phosphorylates p53 causing up regulation of p21, 45kd-growth
arrest and DNA damage (GADD45), and mouse double minute
2 homolog (Mdm2) (DeHaan et al., 2001).Thus, activation of ERK
may cause cell cycle arrest allowing time for the repair of cisplatin-
induced DNA damage via p53.
5.6. Cisplatin and jun amino-terminal kinase (JNK)
c-Jun N-terminal kinase or stress activated protein kinase is
activated by various stress stimuli, including DNA damage. Both cis
and trans forms of cisplatin activate the JNK pathway. p73, a
proapoptotic member of p53 forms a complex with JNK leads to
cisplatin induced apoptosis (Jones et al., 2007).
5.7. Cisplatin and p38 mitogen-activated protein kinase (MAPK)
Environmental stress is an important moderator of cisplatin-
induced apoptosis, by activating p38 MAPK family. It has already
been identied that EGFR as a substrate for p38 MAPK and
cisplatin-induced receptor internalization was triggered by p38-
mediated phosphorylation of the receptor (Winograd-Katz et al.,
2006). p38 MAPK has been shown to mediate its effect via p18
(Hamlet), a p38 MAPK-regulated protein, which interacts with p53
and stimulates the transcription of proapoptotic genes PUMA and
NOXA to induce apoptosis (Cuadrado et al., 2007). Therefore, the
p38 MAPK pathway plays a critical role in regulating cisplatin-
induced apoptosis.
5.8. Cisplatin and AKT
Akt belongs to a family of serine/threonine kinases which act
downstream of phosphoinositide 3-kinase (P13K) and plays a
critical role in the cell survival (Brazil and Hemmings, 2001).
It has been demonstrated that cisplatin-induced DNA damage
caused phosphorylation of BAD at ser136 via Akt (Hayakawa
et al., 2000). Basically, BAD is phosphorylated in cells with
 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology () 9

1 cisplatin- induced DNA damage and this BAD phosphorylation is 5.12. Cisplatin modulation of gene expression
2 required for cell viability after cisplatin treatment in both cisplatin
3 resistant and -sensitive cells. Previous study showed that cisplatin- In vitro studies suggest that cisplatin resistance can result from
4 induced DNA damage triggers the phosphorylation of both BAD epigenetic changes at the molecular and cellular levels, including
5 Ser-112 via an ERK cascade and BAD Ser-136 via a PI-3 K-PKB/Akt reduced accumulation of the platinum compounds by either active
6 cascade. Iinhibition of either of these cascades sensitizes ovarian efux/sequestration/secretion or impaired inux, detoxication
7 cancer cells to cisplatin (Hayakawa et al., 2000). by GSH conjugates, metallothioneins and other antioxidants,
8 It has been demonstrated that cisplatin-induced phosphoryla- increased levels of DNA damage repair (nucleotide excision repair
9 tion of BAD Ser-112 is MEK-dependent; while cisplatin-induced and mismatch repair), changes in DNA methylation status, altera-
10 phosphorylation of BAD Ser- 136 is PI-3K-Akt-dependent. In tions of membrane protein trafcking as a result of defective
11 addition, cisplatin induced phosphorylation of both BAD Ser-112 organization and distribution of the cytoskeleton, overexpression
12 and Ser-136 is involved in maintaining cell viability after cisplatin of chaperones, up- or down-regulated expression of microRNA
13 treatment. All these results suggest that the ERK and PI-3K-Akt (miRNA1), transcription factors and small GTPases, inactivation
14 signaling cascades converge at BAD to suppress the apoptotic (Shen et al., 2012).
15 effect of BAD (Hayakawa et al., 2000). As a consequence of reduced uptake or retention, the formation
16 of platinum-DNA adducts is correspondingly decreased, reducing
17 5.9. Cisplatin and signaling for DNA damage cytotoxicity, resulting in more resistance to the platinum com-
18 pound. Signicant reductions in platinum-DNA adduct formation
19 Mutations are caused by several signals associated with stress. (9-fold) and ribosomal RNA gene-specic interstrand cross-
20 DNA once is damaged is followed by activation of cell cycle check link formation (12-fold) have been reported in studies with
21 points, there by delaying the cell cycle progression either to repair human hepatoma cisplatin-resistant 7404-CP20 cells. However
22 or to permanently eliminate the cells by inducing cell death. The the removal rates of the total platinum-DNA adducts and gene-
23 response of cells to cisplatin induced DNA damage will decide the specic interstrand cross-links were similar to those in their
24 fate of a cell to live or die (Basu and Krishnamurthy, 2010). parental 7404 cells (Johnson et al., 1996).
25 Cisplatin also induces endoplasmic reticulum stress and
26 5.10. p53 and DNA damage response to cisplatin treatment nucleus-independent apoptotic signaling (Mandic et al., 2003).
27 Because cisplatin is a DNA-damaging agent and an inducer of
28 p53 is a short lived protein, which is activated (phosphoryla- apoptosis, it is reasonable to expect changes in HSPs in the
29 tion) by Ataxia telangiectasia mutated (ATM) on DNA damage development of cellular resistance to the drug. HSP60 was sig-
30 signal. The activated p53 now in turn activates Mdm2, which is E3 nicantly expressed in both human cervical and liver carcinoma
31 ubiquitin ligase. p53 can transactivate genes involved in cell cycle (Shen et al., 2012). Up-regulation of HSP27, HSP70, HSP72, GRP78,
32 progression, DNA repair and apoptosis. p53 can regulate cisplatin and HSP90 have been reported to be involved in CP-r ovarian
33 induced cell death by several mechanisms like: degradation of cancer (Arts et al., 1999; Liu et al., 2002), breast cancer (Vargas-
34 ice-like inhibitory protein (FLIP), direct binding and counter- Roig et al., 1998), colon cancer (Bel et al., 1999), cervical HeLa
35 acting the antiapoptotic function of B-cell lymphoma-extra-large cells (Huang et al., 2000) and laryngeal carcinoma cells (Brozovic
36 (Bcl-xL), over expression of phosphatase and tensin homolog et al., 2001).
37 (PTEN) and inhibition of AMPK (Basu and Krishnamurthy, 2010). The low molecular weight GTP-binding proteins of the Rho
38 Although p53 plays an important role in cisplatin induced DNA family, including RhoA, RhoB, RhoC, and Rac, all belong to the Ras
39 damage response, p53 negative cells also respond to cisplatin tumor suppressor gene family. Reduced expression of small
40 induced DNA damage. This suggests the existence of alternate GTPases such as Rab5, Rac1, and RhoA was detected in human
41 pathway for this event to occur upon stress. cisplatin-resistant cells in association with decreased accumula-
42 tion of radiolabeled compounds (Shen et al., 2004). The ribosomal
43 5.11. Cyclobutanedicarboxylate (c-abl) and DNA damage response protein L36 was found to present cisplatin resistance in human
44 to cisplatin treatment carcinoma cells (Shen et al., 2006). In human breast cancer MCF-7
45 cells, reduced expression of the ribosomal protein P0 was found by
46 c-Abl is tyrosine kinase receptor and contains nuclear localiza- proteomic analysis (Smith et al., 2007). Moreover, ectopic L37 over
47 tion motifs and nuclear export signals. Upon DNA damage, c-Abl is expression can attenuate the DNA damage response mediated by
48 recruited from cytoplasm to nucleus, later associate with and p53 (Llanos and Serrano, 2010).
49 phosphorylates MEK kinase 1. This complex activates jun amino- It has been reported that transcription factors such as Y-box
50 terminal kinase /stress-activated protein kinases (JNK/SAPK) binding protein-1, CCAAT-binding transcription factor 2, activating
51 (Kharbanda et al., 2000). It is also demonstrated that activation transcription factor 4, zinc nger factor 143, the nuclear transcrip-
52 of c-Abl and JNK is conditional upon the recognition of cisplatin tion factor- B, the microphthalmia-associated transcription factor,
53 induced DNA damage by the mismatch repair (MMR) system since the forkhead transcription factor O, and mitochondrial transcrip-
54 c-Abl response is absent in MMR-decient cells (Nehme et al., tion factor A, play a major role in cisplatin resistance (Shen et al.,
55 1999). 2012). It was rst found that the levels of nuclear factor (Erythroid-
56 The MMR/c-Abl binds to p73, a member of p53 family to start Derived 2)-like 2 (Nrf2) expression in Nrf2-decient murine
57 apoptosis (Gong et al., 1999). Phosphorylation and stabilization of embryonic cells and human ovarian cancer SK-OV cisplatin-resis-
58 p73 can increase its proapoptotic function by disassociating from tant cells correlate with the extent of resistance to cisplatin. Loss of
59 p63, another p53 family member (Basu and Krishnamurthy, 2010). Nrf2 or inhibition by siRNA resulted in increased cell death,
60 C-Jun will enhance the p73 stability by binding to transcription co cytotoxicity, and apoptosis in response to cisplatin treatment
61 activator Yap1, preventing proteasomal degradation of p73 and compared with control cells (Cho et al., 2008). Also, increased
62 results in the recruitment of p300 to trigger transcription of expression in GCF2-transfected KB-3-1 cells results in reduced
63 proapoptotic genes (Levy et al., 2008).Cisplatin can trigger clea- RhoA expression, disruption of actin-lamin dynamics, mislocali-
64 vage of c-Abl which is a substrate for caspase and proteolytic zation of the membrane protein MRP1, and reduction in cisplatin
65 cleavage of c-Abl was shown to be important for cisplatin-induced accumulation, leading to 3-fold resistance to cisplatin (Shen et al.,
66 apoptosis (Machuy et al., 2004). 2012).

Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
 10 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology ()
1 5.13. Computational studies of cisplatin
2 diamine) dichloroplatinum(II) using a combination of molecular
3 Cisplatin is one of the most effective anticancer drugs currently
4 in use. Following the nding of its antitumor activity over three
5 decades ago, strong research has been carried out to reveal the
6 details of its cytotoxic activity and to design analogs with reduced
7 side effects (Mantri and Baik, 2006). Recently, computational
8 studies have been conducted to complement experimental works.
9 The hydrolysis process of cisplatin which activates the drug was
10 the goal of past research. cisplatinDNA interactions are the next
11 theoretical studies, since DNA is the primary target of the drug.
12 At present, to study the thermodynamics and kinetics of not only
13 cisplatinDNA complexes, but also of other complexes such as Pt
14 (II)-based cisplatin analogs, other transition metal complexes, and
15 DNA binding organic molecules, both quantum mechanical and
16 molecular mechanical methods are being used. Future research is
17 aiming at elucidating the role of repair enzymes in modulating the
18 cytotoxic activity of DNA binding agents (Mantri and Baik, 2006).
19 The combination of dramatically improved computer hardware
20 and robust, sophisticated, and numerically efcient modeling software
21 has allowed for employing high levels of theory to examine various
22 aspects of cisplatin chemistry using computational chemistry techni-
23 ques. The very rst computational studies on cisplatin aimed at better
24 understanding the hydrolysis of cisplatin, because the activation by
25 hydrolysis had long been established as the rate-limiting step (Basch
26 et al., 1986). An intriguing question had been the preferential
27 antitumor activity of the cis isomer over the trans isomer, a fact then
28 attributed to the steric effects of binding DNA bases. It was eventually
29 discovered that the cis orientation of the leaving groups allowed
30 binding of two adjacent guanine bases on the same strand, which
31 resulted in a large kink in the DNA helix, causing polymerases to be
32 stalled at the kink. However, it was demonstrated that the trans
33 isomer is favored over the cis isomer in all cases due to reduction in
34 ligandligand repulsion, especially in the case of anionic ligands. These
35 differences become negligibly small when favorable hydrogen bonding
36 interactions are possible between the ammine ligands and the other
37 labile ligands (Basch et al., 1986).
38 There is increasing awareness now that one important reason
39 for cisplatin's performance is associated to the high mobility group
40 (HMG) proteins that bind to DNA and protect the drugDNA
41 adducts against excision repair (Wang and Lippard, 2005). To
42 enable comparison of the binding of Pt(II) to various positions in
43 the four nucleobases in DNA and to keep computational costs to a
44 minimum, Pt(NH3)23 was used as the fragment that interacted
45 with the bases. The ranking of the bases followed the order: G(N7)
46 4C(N3)4C(O2)4G(O6)4A(N3)EA(N1)4A(N7)4G(N3)4T(O4)
47 4T(O2), based on differential Pt(II) binding energies. On the basis of
48 the ranking above and the fact that most of the potential binding
49 sites are in reality unavailable for binding due to WatsonCrick
50 base pairing, the N7 position of guaninein particular intrastrand
51 binding to two adjacent guanineswas conrmed as the preferred
52 binding site, in full agreement with experimental evidence (Mantri
53 and Baik, 2006)
54 Density functional theory was applied to provide new insights
55 into the structure and reactivity of cis- and transplatin and related
56 hydrolysis product (Carloni et al., 2000) and also to compare the
57 electronic structures of cisplatin and its second-generation analog
58 carboplatin (Carloni and Andreoni, 1996). Results suggested that
59 the replacement of the chloride ligands of cisplatin by carboxylate
60 ligands in carboplatin resulted in a greater stability of the metal-
61 ligand bonds in the latter, leading to potentially higher activation
62 energy for substitution reactions. Later, a more comprehensive
63 study comparing the geometric, electronic, and vibrational proper-
64 ties of cisplatin using different basis sets, including pure ECP and
65 hybrid ECP with various electron correlation methods up to the
66 MP4 level, and DFT, was performed (Pavankumar et al., 1999).
Please cite this article as: Dasari, S., Bernard Tchounwou, P., Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J
Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
Thermodynamics of hydrolysis of cisplatin and bis(ethylene-
mechanics for obtaining optimized geometries of the reactants
and products, and the extended Huckel method for deriving
charge distributions and electronic energies were studied. This
hydrolysis was studied by several others using various levels of
theory, where a common approach adopted has been to use DFT to
optimize the geometries of the key intermediates and reevaluate
their energies using higher level ab initio methods, and/or adding
solvation corrections based on continuum dielectric models.
describes the interaction of transplatin and the fragments trans-
PtCl2(NH3) and Pt(NH3)23 with G:C and A:T base pairs using DFT,
followed by an MP2-based energy analysis (Nikolov et al., 1994;
Mantri and Baik, 2006; Zhang et al., 2001; Lau and Deubel, 2005).
Cisplatin has been known to bind to guanine with much greater
preference over adenine, which is somewhat surprising because it
could be argued that the inductive effects of the electron-
withdrawing oxo group at the C6 position of guanine should
reduce the electron density at N7 compared to adenine that has
an electron-donating amino group at the C6 position, thus making
the N7 of guanine less nucleophilic compared to adenine (Mantri
and Baik, 2006). The major difference between guanine and
adenine is that N1 of guanine is protonated, while adenine
exposes an N1 lone pair. The presence of the N1 proton diminishes
the delocalization of electron density over the nitrogen lone pairs
of the purine skeleton resulting in greater localization of electron
density on the N3 and N7 atoms of guanine, compared to adenine
where the electron density is delocalized over the N1, N3, and N7
atoms (Mantri and Baik, 2006). In an attempt to identify yet
another subtle electronic feature that could help in distinguishing
between the reactivity of adenine and guanine, it was discovered
that the [Pt] fragment is a poor -donor; thus -back donation
does not appear to play a major role (Mantri and Baik, 2006).
Cisplatin binds to other cellular components, resulting in either
deactivation of the drug and/or disruption of normal biochemical
pathways. Thus, signicant efforts have focused on understanding
the binding of cisplatin with other entities found in the cells; in
particular S- and N-containing ligands that are expected have the
greatest afnity for platinum based on good hardness- softness
matching. It was reported a thorough DFT study which compared
the PtL bond strengths of a series of tri- ammine platinum(II)
complexes with oxygen-, nitrogen- and sulfur-donor ligands as
models of competing ligands encountered in a biological system
(Deubel, 2002). In another study, the kinetics of the substitution
reaction of various nitrogen- and sulfur ligands with the activated
cisplatin complex was modeled using DFT. This study revealed that
kinetically N-donor ligands were preferred over S-donors, with the
selectivity originating from electrostatic rather than orbital-based
interaction (Deubel, 2004).
Other areas of active study on cisplatin are degree of local
bending/unwinding upon cisplatin binding, the disruption of base
stacking and other local distortions, the thermodynamics of the
various possible adducts, the directional preference in the forma-
tion of the bifunctional adducts, the ineffectiveness of transplatin,
the effect of cisplatin binding on the dynamics of DNA, and the
binding and recognition of HMG domain and/or DNA repair
proteins to these adducts (Mantri and Baik, 2006). Computational
models have made signicant contributions to understanding the
nature and reactivity of cisplatin and allowed for delineating many
features of how it binds to DNA.
6. Toxicological effects of cisplatin
Cisplatin interacts with DNA, and forms covalent adduct with
purine DNA bases and this platinum compound, interaction is the
 S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology () 11

1 root cause for cytotoxic effect of cisplatin (Yousef et al., 2009). suggesting an active accumulation of drug by renal parenchymal
2 Cisplatin treatment has been associated with several toxic side cells. Studies in recent years have identied two different mem-
3 effects including nephrotoxicity (de Jongh et al., 2003), hepato- brane transporters capable of transporting cisplatin into cells: Ctr1
4 toxicity and Cardiotoxicity (Al-Majed, 2007). Many cardiac events and OCT2 (Ishida et al., 2002). Later, cisplatin is biotransformed in
5 have been reported in many case reports including electro- the kidney into cysteinyl glycine conjugates and other high thiols
6 cardiographicchanges, arrhythmias, myocarditis, cardiomyopathy by some localized enzymes.
7 and congestive heart failure (Yousef et al., 2009). Decrease
8 in antioxidant defense system is reported due to oxidative stress 6.4. Other organ toxicity
9 through the generation of reactive oxygen species, including
10 antioxidant enzymes and non enzymatic molecules, reduced Other cisplatin-induced organ toxicities such as ototoxicity,
11 glutathione, are major alterations in the cisplatin toxicity (Kart gastrotoxicity, myelosuppression, allergic reactions and some
12 et al., 2010). reproductive toxic effects have also been reported (Hartmann
13 et al., 2000; Hartmann and Lipp, 2003)
14 6.1. Hepatotoxicity
15
16 High dosage of cisplatin may lead to hepatotoxicity (dos Santos 7. Conclusions
17 et al., 2007).Oxidative stress is the main reason for cisplatin-
18 induced toxicity possibly due to depletion of reduced glutathione Cisplatin is one of the most effective anticancer agents widely
19 GSH (Yilmaz et al., 2004), also many studies reported that there used in the treatment of solid tumors. It has been extensively used
20 were a signicant elevation in the hepatic malonaldehyde (MDA) for the cure of different types of neoplasms including head and
21 and reduction in the level of antioxidant enzymes in rats treated neck, lung, ovarian, leukemia, breast, brain, kidney and testicular
22 with cisplatin (Yilmaz, et al., 2005; Mansour et al., 2006). The most cancers. In general, cisplatin and other platinum-based com-
23 sensitive biomarkers directly concerned in causing the cellular pounds are considered as cytotoxic drugs which kill cancer cells
24 damage and toxicity are transaminases, because they are cyto- by damaging DNA, inhibiting DNA synthesis and mitosis, and
25 plasmic in location and are released into the circulation after inducing apoptotic cell death. Several molecular mechanisms of
26 cellular damage. Elevation of the hepatic enzymes level in serum action including induction of oxidative stress as characterized by
27 and bilirubin are the indicators for impaired liver functions (Iseri reactive oxygen species production and lipid peroxidation, induc-
28 et al., 2007). Cisplatin hepatotoxicity was shown to be exacerbated tion of p53 signaling and cell cycle arrest, down-regulation of
29 by increased expression of cytochrome P450-2E1 enzyme (Caro proto-oncogenes and anti-apoptotic proteins, and activation of
30 and Cederbaum, 2004).Observed histopathological changes will be both intrinsic and extrinsic pathways of apoptosis. However,
31 necrosis and degeneration of hepatocytes with inammatory cells cisplatin chemotherapy is also associated with substantial side
32 inltration around portal area with sinusoidal dilatation (Kart effects that include hepatotoxic, nephrotoxic, cardiotoxic, neuro-
33 et al., 2010; Cetin et al., 2006). Recent studies have focused on toxic and/or hematotoxic damage. Also, some patients may relapse
34 methods for protection of cisplatin-induced Hepatotoxicity using from cisplatin treatment with their cancers being refractory to
35 various agents, such as selenium (Liao et al., 2008) and vitamin E cisplatin regimen. Hence, combination therapies of cisplatin with
36 (Naziroglu et al., 2004; Iraz et al., 2005). other drugs are common practice in the treatment of human
37 cancers. Findings of several studies have suggested that other
38 6.2. Cardiotoxicity compounds combined with cisplatin constitute the best therapeu-
39 tic approach to overcome drug resistance and reduce the undesir-
40 Leakage of lactate dehydrogenase (LDH) and creatine kinase able side effects. Moving forward, combinatorial strategies which
41 (CK) from cardiac myocytes is due to cardiotoxicity could be a target multiple mechanisms, such as reducing cisplatin uptake and
42 secondary event following cisplatin-induced lipid peroxidation of reducing inammation, may offer the best chance for clinically
43 cardiac membranes. Degeneration and necrosis of cardiac muscle meaningful prevention.
44 ber cells with brous tissue reaction and vacuolated cytoplasm of
45 many muscle cells and blood vessels are inated with blood are
46 the histological changes of cisplatin induced toxicology (Al-Majed Uncited references Q2
47 et al., 2006).
48 (Hayakawa et al. (2004), Hazardous (2014), Ohta et al., (2006);
49 6.3. Nephrotoxicity The chemical book data base (2014))
50
51 The kidney accumulates cisplatin to a greater degree than other
52 organs and is the major route for its excretion. The cisplatin Acknowledgments
53 concentration in proximal tubular epithelial cells is about 5 times
54 the serum concentration (Kuhlmann et al., 1997).The dispropor- The research described in this publication was made possible Q4
55 tionate accumulation of cisplatin in kidney tissue contributes to by a grant from the National Institutes of Health (Grant no.
56 cisplatin-induced nephrotoxicity (Arany and Sarstein, 2003). G12MD007581) through the RCMI Center for Environmental
57 Biosynthesis of amino acid lysine and methionine yields a qua- Health at Jackson State University.
58 ternary ammonium compound called Carnitine, which is required for
59 the transport of fatty acids from the cytosol into the mitochondria
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Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
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Pharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.07.025i
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