cisplatin.pdf

Review

Cisplatin in cancer therapy: Molecular mechanisms of action

Shaloam Dasari, Paul Bernard Tchounwou n

Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD RCMI-Center for Environmental Health, College of Science,Engineering and Technology, Jackson State University, 1400 Lynch Street, Box 18750, Jackson, MS 39217, USA

a r t i c l e i n f o

Article history:Received 27 March 2014Received in revised form13 July 2014Accepted 14 July 2014Available online 21 July 2014

Keywords:CisplatinPlatinum-based drugsMechanisms of actionCancer treatment

a b s t r a c t

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug.It has been used for treatment of numerous human cancers including bladder, head and neck, lung,ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germcell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink withthe purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, andsubsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerousundesirable side effects such as severe kidney problems, allergic reactions, decrease immunity toinfections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, otherplatinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used.Furthermore, combination therapies of cisplatin with other drugs have been highly considered toovercome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochem-ical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or incombination with other drugs) for the treatment of various human cancers. A special attention is paid toits molecular mechanisms of action, and its undesirable side effects.

& 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3652. Cisplatin and other platinum-containing drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3653. Uses of cisplatin for cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

3.1. Cisplatin and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3673.2. Cisplatin and ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3673.3. Cisplatin and carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3673.4. Cisplatin and breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3673.5. Cisplatin and brain cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

4. Combination therapy of cisplatin with other cancer drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3674.1. Cisplatin and paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3674.2. Cisplatin and tegafur-uracil (UFT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3684.3. Cisplatin and doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3684.4. Cisplatin and gemcitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3684.5. Cisplatin and vitamin D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3684.6. Other possible drug combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368

5. Molecular mechanisms of cisplatin pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3695.1. Cisplatin-induced oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3695.2. Cisplatin modulation of calcium signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3705.3. Cisplatin-induced cell apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3715.4. Cisplatin and protein kinase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3715.5. Cisplatin and mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3715.6. Cisplatin and jun amino-terminal kinase (JNK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/ejphar

European Journal of Pharmacology

http://dx.doi.org/10.1016/j.ejphar.2014.07.0250014-2999/& 2014 Elsevier B.V. All rights reserved.

n Corresponding author. Tel.: 1 601 979 0777.E-mail address: [email protected] (P. Bernard Tchounwou).

European Journal of Pharmacology 740 (2014) 364378

5.7. Cisplatin and p38 mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3715.8. Cisplatin and AKT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3715.9. Cisplatin and signaling for DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3725.10. p53 and DNA damage response to cisplatin treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3725.11. Cyclobutanedicarboxylate (c-abl) and DNA damage response to cisplatin treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3725.12. Cisplatin modulation of gene expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3725.13. Computational studies of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

6. Toxicological effects of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3746.1. Hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3746.2. Cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3746.3. Nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3746.4. Other organ toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

1. Introduction

Cisplatin (CAS no. 15663-27-1, MF-Cl2H6N2Pt; NCF-119875),cisplatinum, also called cis-diamminedichloroplatinum(II), is ametallic (platinum) coordination compound with a square planargeometry (The chemical book database, 2014). It is a white or deepyellow to yelloworange crystalline powder at room temperature.It is slightly soluble in water and soluble in dimethylprimanideand N,N-dimethylformamide. Cisplatin is stable under normaltemperatures and pressures, but may transform slowly over timeto the trans-isomer (IARC, 1981; Akron, 2009). Cisplatin has amolecular weight of 301.1 g/mol, a density of 3.74 g/cm3, a meltingpoint of 270 1C, a log Kow of 2.19 and a water solubility of 2.53 g/L at 25 1C (HSDB, 2014).

Cisplatin was rst synthesized by M. Peyrone in 1844 and itschemical structure was rst elucidated by Alfred Werner in 1893.However, the compound did not gain scientic investigations untilthe 1960s when the initial observations of Rosenberg et al. (1965)at Michigan State University pointed out that certain electrolysisproducts of platinum mesh electrodes were capable of inhibitingcell division in Escherichia coli created much interest in thepossible use of these products in cancer chemotherapy. Since theidentication of cis-dichlorodiammineplatinum (II) (cisplatin, r) asthe agent responsible for this activity, considerable interest hasbeen generated in the use of coordination complexes of platinum,palladium, and other noble metals in the treatment of cancer.

Cisplatin has been especially interesting since it has shownanticancer activity in a variety of tumors including cancers of theovaries, testes, and solid tumors of the head and neck. It wasdiscovered to have cytotoxic properties in the 1960s, and by theend of the 1970s it had earned a place as the key ingredient in thesystemic treatment of germ cell cancers. Among many chemother-apy drugs that are widely used for cancer, cisplatin is one of themost compelling ones. It was the rst FDA-approved platinumcompound for cancer treatment in 1978 (Kelland, 2007). This hasled to interest in platinum (II)and other metalcontaining com-pounds as potential anticancer drugs (Frezza et al., 2010).

Cisplatin is clinically proven to combat different types of cancersincluding sarcomas, cancers of soft tissue, bones, muscles, and bloodvessels. Although such cancers have recently received better prog-nosis and therefore have become less life threatening (Desoize andMadoulet, 2002), signicant challenges remain with regard to theircure. Also, because of drug resistance and considerable side effects,combination therapy of cisplatin with other cancer drugs has beenapplied as novel therapeutic strategies for many human cancers. Inthis research, we aim to provide a comprehensive review of thephysicochemical properties of cisplatin and related platinum-baseddrugs, to discuss its uses (either alone or in combination with other

drugs) for the treatment of various human cancers, to examineits molecular mechanisms of action, and to discuss it potentialside effects.

2. Cisplatin and other platinum-containing drugs

Since the early seminal work in the preclinical and clinicaldevelopment of cisplatin, several thousand analogs have beensynthesized and tested for properties that would enhance itstherapeutic index. About 13 of these analogs have been evaluatedin clinical trials, but only one (carboplatin) has provided deniteadvantage over cisplatin and achieved worldwide approval. Nineplatinum analogs are currently in clinical trials around the worldormaplatin (tetraplatin), oxaliplatin, DWA2114R, enloplatin, loba-platin, CI-973 (NK-121), 254-S, JM-216, and liposome-entrappedcis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (LNDDP)] (Weiss and Christian, 1993). Fig. 1 presents thechemical structures of cisplatin and four of its analogs includingcarboplatin, oxaliplatin, ormaplatin and enloplatin.

From the molecular perspective, cisplatin represents a perfectexample of how a small alteration in chemical structure cansignicantly affect biological activity in target cell (Goodsell,2006). As illustrated in Fig. 2, cisplatin, carboplatin and oxalipla-tin are composed of doubly charged platinum ion surrounded byfour ligands, with the amine ligands on the left forming strongerinteractions with the platinum ion, and the chloride ligandsor carboxylate compounds on the right forming leaving groupsallowing the platinum ion to form bonds with DNA bases(Goodsell, 2006).

Carboplatin or Cis diammine (1,1-cyclobutanecarboxylato) pla-tinum (II) is a chemotherapeutic drug used for cancers of ovaries,lung, head and neck. In terms of its structure, carboplatin differsfrom cisplatin in that it has a bidentate dicarboxylate (CBDCA)ligand in place of the two chloride ligands, which are the leavinggroups in cisplatin (Figs. 1 and 2). It exhibits lower reactivityand slower DNA binding kinetics, although it forms the samereaction products in vitro at equivalent doses with cisplatin. Unlikecisplatin, carboplatin may be susceptible to alternative mechan-isms. Some studies show that cisplatin and carboplatin causedifferent morphological changes in MCF-7 cell lines while exertingtheir cytotoxic behavior (Natarajan et al., 1999). The dimin-ished reactivity limits proteincarboplatin complexes, which areexcreted. The lower excretion rate of carboplatin means that moreis retained in the body, and hence its effects are longer lasting(a retention half-life of 30 h for carboplatin, compared to 1.53.6 hin the case of cisplatin).

S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364378 365

Relative to cisplatin, the greatest benet of carboplatin is itsreduced side effects, particularly the elimination of nephrotoxiceffects. The main drawback of carboplatin is its myelo suppressiveeffect which causes the blood cell and platelet output of bonemarrow in the body to decrease quite dramatically, sometimes aslow as 10% of its usual production levels (Canetta et al., 1985).

Carboplatin is less potent than cisplatin; depending on the type ofcancer, carboplatin may only be 1/8 to 1/45 as effective. The clinicalstandard of dosage of carboplatin is usually a 4:1 ratio compared tocisplatin; that is, for a dose that usually requires a particular dose ofcisplatin, four times more carboplatin is needed to achieve the sameeffectiveness. The stable property of carboplatin is a mixed blessing;once uptake of the drug occurs, its retention half-life is considerablylonger than cisplatin, but it is also this inertness that causescarboplatin to go right through the human body, and up to 90% ofthe carboplatin given can be recovered in urine (Go and Adjei, 1999).

In order to overcome cisplatin resistance, other platinum (Pt)compounds have been developed and, in the last ten years,Pt-derivatives with reporting activity have also been synthesized.The rst generation of reporting Pt-compounds was based onlinking a uorescent molecule (e.g. cyanine) to cisplatin, but morerecent studies have focused on strategies to synthesize intrinsi-cally uorescent derivatives. Accordingly, bile acid platinum com-pounds have shown uorescence intensity that is stable at roomtemperature for a long time; this uorescence is maintained afterbinding to oligonucleotides or DNA. Because of this, the bindingmode of these compounds to DNA can be easily analyzed both byow injection and uorescence techniques, showing that althoughthese compounds target the nuclei, they form adduct with theDNA that are different from those due to cisplatin. In line with this,these bile acid derivatives have shown increased cytotoxicity andability to overcome resistance as compared to cisplatin in severalcell lines. Moreover, in contrast to cisplatin, the activity of thesecompounds does not seem to be restricted to cycling cells but theyalso seem to kill resting cells (Rodriguez-Fernandez et al., 2009)

Fig. 1. Chemical structures of selected platinum drugs: A-cisplatin; B-carboplatin; C-oxaliplatin; D-ormaplatin; E-enloplatin (Weiss and Christian, 1993).

Fig. 2. Computational molecular structures of cisplatin, carboplatin and oxalipla-tion. These platinum compounds are composed of doubly charged platinum ionsurrounded by four ligands; with the amine ligands on the left forming strongerinteractions with the platinum ion, and the chloride ligands or carboxylatecompounds on the right forming leaving groups allowing the platinum ion to formbonds with DNA bases (Goodsell, 2006).

S. Dasari, P. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364378366

3. Uses of cisplatin for cancer treatment

3.1. Cisplatin and lung cancer

Lung cancer remains one of the most common types of fatalmalignancies (Youlden et al., 2008). Small cell lung cancers (SCLCs)represent 15% of all lung cancers (Chen et al., 2009). At present,platinum based treatments are key drugs for SCLC (Abrams et al.,2003). Cisplatin and carboplatin are two of the most commontypes of platinum based treatments used in SCLC chemotherapy(Go and Adjei, 1999). In clinical trials, cisplatin is often selecteddue to its strong antitumor activity, but its adverse effects includerenal toxicity (Iwasaki et al., 2005), nausea and vomiting (Kosmaset al., 2001). Therefore, to avoid renal toxicity, urine volumesshould be monitored and large-dose infusion is mandatory incisplatin based chemotherapy. In clinical practice, carboplatin hasbeen considered to be a substitute for cisplatin without anyapparent loss of therapeutic efcacy since aggressive hydration isoften problematic.

The standard of care for localized non-small-cell lung cancer(NSCLC) is surgery followed by, in case of stage II and III disease,adjuvant cisplatin-based chemotherapy. The Lung AdjuvantCisplatin Evaluation program, a pooled analysis of the ve largesttrials, recently showed an absolute 5-year survival benet of 5.3%with adjuvant chemotherapy as well as the NSCLC meta-analysis(Pignon et al., 2008).

CD133, a surface glycoprotein linked to organ-specic stemcells, has been described as a marker of cancer-initiating cells indifferent tumor types. It has also been reported that a CD133 ,epithelial-specic antigen-positive (CD133ESA) population isincreased in primary non-small cell lung cancer (NSCLC) comparedwith normal lung tissue (Bertolini et al., 2009).

3.2. Cisplatin and ovarian cancer

Ovarian cancer has the highest mortality among gynecologiccancers. Most patients with ovarian cancer are diagnosed at latestages due to lack of effective screening strategies and specicsymptoms associated with early-stage disease. Conventional treat-ment for late stages of ovarian cancers is surgical excision followedby platinum/taxane combination chemotherapy. Although thistreatment regime is effective as the rst-line treatment, recur-rence occurs in up to 75% of ovarian cancer patients. Patientswith recurrent ovarian cancer ultimately develop resistance tochemotherapy and eventually succumb to the disease (Agarwaland Kaye, 2003). About 90% of ovarian cancers arise originallyfrom ovaries with an unknown reason, while the remainder hashereditary background, or are associated with breast and coloncancers (Lynch et al., 2009). Cisplatin derivatives are used as themainline treatment of ovarian cancer, despite their severe sideeffects and development of resistance. Cisplatin is used in combi-nation with other chemical agents or compounds to treat ovariancancer in both the resistant and sensitive cell lines. For examplecisplatin is used along with honey venom (Alizadehnohi et al.,2012), withaferin (Kakar et al., 2012), trichostatin A or 5-aza-20-deoxycytidine (Meng et al., 2013), overcoming chemotherapyresistance of ovarian cancer cells by liposomal cisplatin (Kochet al., 2013)

3.3. Cisplatin and carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a commonmalignant disease with more than 600,000 new cases registeredworldwide every year (Parkin et al., 2005). Despite improvedtreatment options, including surgery, radiation and chemotherapy,HNSCC is associated with a high mortality rate. The overall 5-year

survival rate of approximately 50% has not changed over the lastdecades. Cisplatin alone is not an effective drug in treating thedisease. A randomized comparison of cisplatin alone or in combi-nation with methotrexate, vinblastine, doxorubicin, and or gemci-tabine in patients with metastatic urothelial carcinoma has beenreported (Scher, 1992; Matsuki et al., 2013).

3.4. Cisplatin and breast cancer

Breast cancer is one of the leading causes of women mortalityworldwide. Chemotherapy is the only option for treating themalignant breast cancer and condition for increases the lifespanof the patient (Decatris et al., 2004). Chemotherapeutic agentshave been developed to counter the continuing breast cancerproblem. However, most chemotherapeutic drugs effectively tar-get rapidly dividing cells causing damage and are thus referred toas cytotoxic drugs. Cisplatin is an important chemotherapeuticagent used widely or the treatment of a variety of malignancies,including breast, testicular, ovarian, cervical, prostate, head andneck, bladder, lung and refractory non-Hodgkin's lymphomas(Tsimberidou et al., 2009; Dhar et al., 2011). The cytotoxic effectis likely a result of inhibition of replication by cisplatin-DNAadducts and induction of apoptosis (Siddik, 2003).

3.5. Cisplatin and brain cancer

Glioblastomamultiforme (GBM) is the most common primarymalignant brain tumor, and with rare exception, is invariably fatal(Stupp et al., 2005). The current standard of care for patientswith GBMs consists of surgery and radiotherapy in combinationwith temozolomide, followed by repetitive cycles of temozolo-mide (Stupp et al., 2009). Although the survival advantage ofthis combined treatment regimen was still evident at 5 years, theincrease in overall median survival was only for 2.5 months.Cisplatin therapy is also used for recurrent childhood braintumors(Khan et al., 1982),as well as in other cancers such asgastric cancer (Koizumi et al., 2008), anal cancer (Ajani et al.,2008), and leukemia (Previati et al., 2006).

4. Combination therapy of cisplatin with other cancer drugs

Cisplatin combination chemotherapy is the basis of treatmentof many cancers. Platinum responsiveness is high primarilybut many cancer patients will ultimately relapse with cisplatin-resistant disease. Hence, drug resistance has been observed inmany patients who have relapsed from cisplatin treatment. Theproposed mechanisms of cisplatin resistance include changes incellular uptake and efux of cisplatin, increased biotransformationand detoxication in the liver, and increase in DNA repair and anti-apoptotic mechanisms (Gottesman et al., 2002). To overcomeresistance, cisplatin is commonly used in combination with someother drugs in treating ovarian cancer, biliary tract cancer, lungcancer (diffuse malignant pleural mesothelioma), gastric cancer,carcinoma of salivary gland origin, breast, colon, lung, prostate,melanoma and pancreatic cancer cell lines, squamous cell carci-noma of male genitial tract, urothelial bladder cancer, and cervicalcancer. Table 1 presents a synopsis of cisplatin combinationtherapy with other cancer drugs and targeted cancers.

4.1. Cisplatin and paclitaxel

Paclitaxel is a mitotic agent that binds preferentially to micro-tubules (Parness et al., 1981) and the resulting stabilizationof microtubules inhibits the reorganization of the microtubulenetwork. Paclitaxel has been demonstrated to be active against


previously treated ovarian carcinoma (Sarosy et al., 1992; McGuireet al., 1989; Einzig et al., 1992), breast carcinoma (Holmes et al.,1991), lung carcinoma (Murphy et al., 1993), and melanoma (Leghaet al., 1990; Einzig et al., 1991) as well as for head and neckcarcinoma (Forastiere, 1994). The combination chemotherapy withpaclitaxel, cisplatin and uorouracil is an active and tolerable asrst-line and second line therapies in Chinese patients withadvanced gastric and esophagogastric junction adenocarcinomawhich showed a better tolerance has also been reported (Kim etal., 1999)

4.2. Cisplatin and tegafur-uracil (UFT)

UFT is an oral anticancer agent comprised of tegafur and uracilin a 1:4 xed molar ratio and is absorbed very well from the smallintestine (Fujii et al., 1979). Combination chemotherapy comprisedof oral UFT (a combination of tegafur and uracil) and cisplatin wasshown to be an effective regimen for the treatment of advancednon-small cell lung carcinoma (Ichinose et al., 2000).

4.3. Cisplatin and doxorubicin

The combination of doxorubicin and cisplatin is effective andwell tolerated. It might be considered for palliation of symptomaticpatients with diffuse malignant pleural mesothelioma DMPM(Ardizzoni et al., 1991). Cyclophosphamide, doxorubicin, and cispla-tin combination chemotherapy for advanced carcinomas of salivarygland origin showed encouraging results (Dreyfuss et al., 1987).

4.4. Cisplatin and gemcitabine

As compared with gemcitabine alone, cisplatin plus gemcita-bine was associated with a signicant survival advantage withoutthe addition of substantial toxicity. Cisplatin plus gemcitabine is anappropriate option for the treatment of patients with advancedbiliary cancer (Valle et al., 2010).

4.5. Cisplatin and vitamin D

Vitamin D and its analogs regulate gene expression by bindingto specic vitamin D receptors (VDR). Upon ligand activation anddimerization with retinoid X receptor (RXR), VDRRXR hetero-dimers bind specic nucleotide sequences, vitamin D responseelements (VDREs), in target genes to activate or repress theirexpression (Baniahmad and Tsai, 1993). A number of vitamin Dtarget genes have been identied in several tumor cell types: p21,E-cadherin, c-Jun N-terminal kinase (JNK), c-Myc oncogene,insulin-like transforming growth factor family and their receptors(Saramaki et al., 2006; Nagpal et al., 2005).

Cisplatin is used along with vitamin D in treating squamous cellcarcinoma (Light et al., 1997) and colon cancer (Milczarek et al.,2013). Published research has shown that pre-treatment for 72 hof human promyelocytic leukemia (HL-60) cells with calcitriol orits new analogs signicantly potentiated their sensitivity to theantiproliferative effect in vitro of cisplatin, doxorubicin or genis-tein. Moreover, for all cytotoxic agents tested a synergistic anti-proliferative effect was observed. This effect was expressed as asignicant decrease of the ID50 (inhibitory dose 50%) values foreach cytotoxic agent applied after pretreatment of HL-60 cellswith calcitriol or its analogs in comparison with the effect ofcytotoxic agent applied alone (Siwinska et al., 2001).

4.6. Other possible drug combinations

Cisplatin is also used in combination with natural compoundslike osthole in lung cancer cell lines (Xu et al., 2013), honey beevenom in ovarian cancer cells (Alizadehnohi et al., 2012), anvirzelin breast, colon, lung, prostate, melanoma and pancreatic cancercell lines (Apostolou et al., 2013), bevacizumab in non-small celllung cancer mediated malignant pleural effusion (Du et al., 2013),vinblastine and bleomycin in metastatic granulosa cell tumor ofthe ovary (Colombo et al., 1986), methotrexate, bleomycin andcisplatin for advanced squamous cell carcinoma of the male genitaltract (Dexeus et al., 1991).

Table 1Combination therapy of cisplatin and other cancer drugs.

Combination drug(s) Cancer type Reference(s)

Paclitaxel Ovarian carcinoma, breast carcinoma, lung carcinoma,melanoma, head and neck carcinoma

Sarosy, Kohn et al. (1992),McGuire et al. (1989),Einzig et al. (1992),Holmes et al. (1991),Murphy et al. (1993),Legha et al. (1990), Einzig et al. (1991), Forastiere (1994)

Paclitaxel and 5-FU Gastric and esophagogastric adenocarcinoma Kim et al. (1999)UFT Non small lung carcinoma Ichinose et al. (2000)Doxorubicin Diffuse malignant pleural mesothelioma Ardizzoni et al. (1991)Cyclophosphamide and doxorubicin Salivary gland advanced carcinoma Dreyfuss et al. (1987)Gemcitabine Biliary cancer Valle et al. (2010)Osthole Lung cancer Xu et al. (2013)Honeybee venom Ovarian cancer Alizadehnohi et al. (2012)Anvirzel Breast, colon, lung, prostate, melanoma and pancreatic

cancerApostolou et al. (2013)

Bevacizumab Non small lung carcinoma Du et al. (2013)Vinbalstine and bleomycin Metastatic granulosa cell tumors in ovary Colombo et al. (1986)Methotrexate and bleomycin Advanced squamous cell carcinoma of the male

genital tractDexeus et al. (1991)

Everolimus Urothelial bladder cancer Pinto-Leite, et al. (2013)Fluorouracil, doxorubicin andcyclophosphamide

Salivary gland carcinoma Dimery et al. (1990)

Metformin Lung adenocarcinoma Lin et al. (2013)Oxaliplatin, quercetin and thymoquinone Ovarian cancer Nessa et al. (2011)Olaparib PTEN decient lung cancer Minami et al. (2013)Tetra arsenic oxide Cervical cancer Byun et al. (2013)Vindesine Non small lung carcinoma Le et al. (1994)-galactosyl-pyrrolidinyldiazeniumdiolate Glial cells of brain Human cervical cancer

Gliosarcoma cell linesDeng et al. (2013)


Everolimus combined with cisplatin has a potential role intreatment of urothelial bladder cancer (Pinto-Leite et al., 2013),Fluorouracil, doxorubicin, cyclophosphamide, and cisplatin com-bination chemotherapy has been used in advanced or recurrentsalivary gland carcinoma (Dimery et al., 1990). Metformin has beenshown to enhance cisplatin cytotoxicity by suppressing Stat3activity independently of the LKB1-AMPK pathway (Lin et al.,2013).

Synergistic interactions have been reported for -galacto-syl-pyrrolidinyldiazeniumdiolate and cisplatin combinationchemotherapy against glial cells of brain, human cervical andgliosarcoma cell lines (Deng et al., 2013). Cisplatin and oxaliplatinin combination with quercetin and thymoquinone in humanovarian tumour models is the best combination to treat ovariancancer (Nessa et al., 2011). Olaparib in combination with cisplatinhas a synergistic effect on PTEN-Decient lung cancer Cells(Minami et al., 2013). Tetraarsenic oxide and cisplatin induceapoptotic synergism in cervical cancer (Byun et al., 2013). Vinde-sine and cisplatin combination chemotherapy compared withvindesine as a single agent in the management of non-small celllung cancer seemed to be more effective (Le et al., 1994).

In ovarian carcinoma treatment, the combination of cisplatinand paclitaxel produced a more encouraging response rate (73%)(McGuire et al., 1996). A single institutional Phase II trial usingcisplatin and oral UFT administration in place of protractedintravenous injection of 5-FU yielded a 35% response rate and amedian survival time of 11 months in 31 patients with advancedNSCLC (Ichinose et al., 1995). The addition of cisplatin to cyclopho-sphamide and doxorubicin (CAP) has been recently associatedwith overall response rates of 5700% and complete response ratesof 2675% in small series of patients (Creagan et al., 1983; Albertset al., 1981; Eisenberger, 1985). Cisplatin is known to have anadditive or synergistic effect in combination with gemcitabine in anumber of different tumor types (Crino et al., 1997; von der et al.,2005; Hitt et al., 1998).

Photodynamic therapy (PDT), which is the administration of aphotosensitiser followed by visible light activation, is a promisingroute to avoid damage to healthy cells and the surrounding tissue.Transition metal complexes as photochemotherapeutic agents arean attractive option for further development in the eld ofphotoactivated chemotherapy (PACT). These complexes exhibitdifferent numbers and types of excited states which are easilyaccessible upon light irradiation, subsequently giving rise to theformation of various photoproducts that can enable a distinctmode of action. Platinumdiazido complexes are promising can-didates for PACT due to the low cytotoxicity when irradiated withvisible light (Shaili, 2014).

Cisplatin resistance is correlated with autophagy induction ina panel of ovarian cancer cells (Wang and Wu, 2014). Previousstudies demonstrated that A549/CDDP cells acquired an epithelial-mesenchymal transition (EMT) phenotype, with morphologicalchanges including acquisition of a spindle-like broblastic pheno-type, downregulation of E-cadherin, upregulation of mesenchymalmarkers (vimentin, Snail and Slug), and increased capability ofinvasion and migration in case of human lung cancer cell lines.(Demonstrated that A549/CDDP cells acquired an epithelial-mesenchymal transition (EMT) phenotype, with morphologicalchanges including acquisition of a spindle-like broblastic pheno-type, downregulation of E-cadherin, upregulation of mesenchymalmarkers (vimentin, Snail and Slug), and increased capability ofinvasion and migration in case of human lung cancer cell lines(Wang et al., 2014).

It has been hypothesized that Rac1, a Rho GTPase, is implicatedin HNSCC insensitivity to chemo-radiotherapy resulting in tumourrecurrence development in head and neck squamous cell carci-noma (Skvortsov et al., 2014). Cisplatin resistance in colorectal

cancer is due to adaptive activation of Nrf2 may contribute to thedevelopment of acquired drug-resistance (Chian et al., 2014). It isalso indicated that AQP5 is associated with drug resistance ofcolon cancer (Shi et al., 2014). In chondrosarcoma cells over-expression of EGFR contributed to cisplatin resistance (Song etal., 2014). Due to loss of homeodomain-interacting protein kinase-2 (HIPK2) contributes to cell proliferation and tumorigenesis inbladder 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), andthe solute carrier importers (CTR1, the SLCs, AQP2, and AQP9),have been reported. MDR1 is an ATP-binding cassette transporterknown 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 beenfurther conrmed in human cells that cisplatin triggers rapiddegradation of the copper membrane transporter CTR1, withdiminished inux of cisplatin, resulting in resistance to the drug(Lin et al., 2002; Holzer et al., 2006). Genetic knockout of CTR1results in cellular resistance to cisplatin in vivo. Cells withincreased CTR1 expression exhibit increased platinum accumula-tion and, in most instances, increased sensitivity to cisplatin.TMEM205, a membrane protein has been associated with cellularresistance to cisplatin was identied. Analysis of TMEM205expression 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 inCP-r cells may play a role in cellular resistance to platinum andwould also be valuable as a biomarker or target in cancerchemotherapy (Shen et al., 2012). Glucose Transporter 1 (Glut1)is not proposed to directly transport cisplatin, the mislocalizationof the transporter exacerbates the cisplatin resistance phenotype(Shen et al., 2012).

Cisplatin becomes activated once it enters the cell. In thecytoplasm the chloride atoms on cisplatin are displaced by watermolecules. This hydrolyzed product is a potent electrophile thatcan react with any nucleophile, including the sulfhydryl groups onproteins and nitrogen donor atoms on nucleic acids. Cisplatinbinds to the N7 reactive center on purine residues and as such cancause 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 mostnotable 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-intrastrandd(GpXpG) adducts and other adducts such as inter-strand cross-links and nonfunctional adducts have been reported to contributeto cisplatin's toxicity. Hence, published research from manylaboratories has implicated DNA as a critical target for cisplatincytotoxicity, the most revealing evidence being the hypersensitiv-ity to cisplatin by both prokaryotic and eukaryotic cells decient inDNA repair (Beck and Brubaker, 1973; Fraval et al., 1978). Asillustrated in Fig. 3, several molecular mechanisms leading toapoptosis have been implicated in cisplatin treatment of humancancers.

5.1. Cisplatin-induced oxidative stress

Under normal physiological conditions, cells control reactive oxy-gen species levels by balancing the generation of reactive oxygenspecies with their elimination by scavenging system (reduced


glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT). Butunder oxidative stress conditions, excessive reactive oxygen speciescan damage cellular proteins, lipids and DNA, leading to fatal lesions incells that contribute to carcinogenesis. Cancer cells exhibit greaterreactive oxygen species stress than normal cells do, partly due tooncogenic stimulation, increased metabolic activity and mitochondrialmalfunction. Oxidative stress is the one of most important mechan-isms involved in cisplatin toxicity. The mitochondrion is the primarytarget for cisplatin induced oxidative stress, resulting in loss ofmitochondrial protein sulfhydrl group, calcium uptake inhibition andreduction of mitochondrial membrane potential (Saad et al., 2004)

Exposure to oxidative stress can upset regular biological func-tions. Cisplatin also induces reactive oxygen species that triggercell death besides DNA damage. Cell death occurs upon immediateactivation of numerous signaling pathways, whereas the denitepathways depend on the (cancer) cell. The formation of reactiveoxygen species depends on the concentration of cis-diamminedi-chloro platinum(II) and the length of exposure (Brozovic et al.,2010). The intracellular redox homeostasis is maintained by thethiol group (SH) containing molecules. Under certain conditions athiol group may lead to formation of thiyl radicals that in turn caninteract with molecular oxygen, therefore generating reactiveoxygen species (Desoize, 2002).

Excessive reactive oxygen species can induce apoptosis throughboth the extrinsic and intrinsic pathways (Ozben, 2007). In theextrinsic pathway of apoptosis, reactive oxygen species are gener-ated by Fas ligand as an upstream event for Fas activation viaphosphorylation, which is necessary for subsequent recruitment ofFas-associated protein with death domain and caspase 8 as well asapoptosis induction (Gupta et al., 2012). In the intrinsic pathway,reactive oxygen species function to facilitate cytochrome c releaseby activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well asinhibiting pore-destabilizing proteins (Bcl-2-associated X protein,Bcl-2 homologous antagonist/killer) (Martindale and Holbrook,2002). An even higher reactive oxygen species level can result inboth apoptosis and necrosis in cancer cells (Hampton andOrrenius, 1997). Reactive oxygen species can also induce cell deaththrough autophagy, which is a self-catabolic process involvingsequestration of cytoplasmic contents (exhausted organelles andprotein aggregates), for degradation in lyposomes (Shrivastavaet al., 2011)

5.2. Cisplatin modulation of calcium signaling

Cisplatin, under low intracellular chloride ion concentrations,has been shown to hydrolyze into variously charged reactive

Fig. 3. Overview of molecular mechanisms of cisplatin in cancer treatment.


species including monoaqua [cis-(NH)PtCI(HO)] and diaquated[cis-(NH)Pt(HO)]2 forms (Jennerwein and Andrews, 1995;Aggarwal et al., 1980). These hydrolyzed forms of cisplatin havebeen shown to be 1000 times more reactive than normal cisplatin,and act through the inhibition of mitochondrial respiration byuncoupling oxidative phosphorylation (Aggarwal, 1993). Thisresult in an efux of calcium from the mitochondria and atemporary increase in the cellular calcium levels, which is thoughtto play a signicant role in the disruption of normal calciumhomeostasis, and hence cell function.

Mitochondrial glutathione (GSH) seems to be essential in theregulation of inner mitochondrial permeability and enzyme func-tion by keeping SH in the reduced state. When the SH-groups ofenzymes are not maintained in a reduced form, they becomeinactivated. Cisplatin induced toxicities, especially nephrotoxicity,seem to be related to a decrease in the intracellular concentrationsof GSH and protein bound SH-groups. Nicotinamide adeninedinucleotide (NADH), which helps to maintain SH groups, declineswith cisplatin treatment. Consequently, this depletion of GSH andNADH appears to result in the inhibition of some dehydrogenases,resulting in the uncoupling of oxidative phosphorylation leadingto hydroxyl radical formation and oxidative stress. These freeradicals attack polyunsaturated lipids and proteins and initiatelipid per oxidation. This process becomes autolytic and causessevere damage to membrane integrity (Aggarwal, 1998).

In summary, cisplatin's disruption of calcium homeostasisinitiates primary events such as lipid per oxidation and enzymeinhibition. These events damage the cells through mitochondrialdamage, inhibition of mitochondrial function, depletion of adeno-sine triphosphate (ATP) and other cofactors. This probably leads toapoptosis and tissue necrosis. Thus, it seems that elevated calciumlevels, via calcium supplementation, may act as another means ofcytoprotection, by competing for binding sites with cisplatin andprevent various toxicities associated with it.

5.3. Cisplatin-induced cell apoptosis

Apoptosis is a controlled type of cell death which is energy-dependent leading to cell shrinkage, chromatin condensation,membrane budding, phosphatidylserine externalization, and acti-vation of a family of cysteine proteases called caspases (Salvesenand Dixit, 1997; Cummings et al., 2000). Caspase activation is thekey step in the beginning of apoptosis, and several stimuli activatecaspases, including those that activate plasma membrane deathreceptors (caspase 8) and cause mitochondrial dysfunction (cas-pase 9). Caspases are either initiators or executioners of apoptosis.Initiator caspases include caspases 8 and 9, and activation of thesecaspases results in activation of downstream or executionercaspases such as caspases 3 and 7 (Salvesen and Abrams, 2004).Executioner caspases are accountable for many of the biochemicalcharacteristics of apoptosis, including cleavage and activation ofpoly (ADP-ribose) polymerase and of the inhibitor of caspaseactivator domain protein, which leads to DNA fragmentation.

Cisplatin primarily induces cell death by apoptosis and a defectin apoptotic signaling could also confer cisplatin resistance. Thereare two major pathways of apoptotic cell death (Nunez et al., 1998;Kischkel et al., 1995). The extrinsic pathway is initiated whenligands bind to the tumor necrosis factor- (TNF) receptor superfamily followed by oligomerization and recruitment of procaspase-8 via adapter molecules to form the death-inducing signalingcomplex (DISC). The intrinsic pathway is initiated by cellularstress, such as DNA damage, resulting in release of cytochrome-cfrom the mitochondria causing activation of procaspase-9 throughthe interaction with apoptosis promoting activating factor-1(APAF-1) and formation of an active apoptosome complex. Bcl-2family proteins regulate DNA damage-induced apoptosis by

regulating the release of mitochondrial cytochrome c in responseto DNA damage. Cisplatin-induced genotoxic stress activatesmultiple signal transduction pathways, which can contribute toapoptosis or chemo resistance.

5.4. Cisplatin and protein kinase C

Protein kinase C [PKC] is a family closely related phospholipiddependent enzymes that play critical roles in signal transductionand cell regulation (Basu and Sivaprasad, 2007; Newton, 2003;Basu, 1993; Nishizuka, 1992). There have been contrasting onreports whether activation or down regulation of PKC is necessaryfor cisplatin sensitization (Isonishi et al., 1990; Hirata et al., 1993).The effects of PKC on cellular sensitivity/resistance to cisplatindepend on the pattern of the PKC isozymes as well as on thecellular context (Basu and Krishnamurthy, 2010).

5.5. Cisplatin and mitogen-activated protein kinase (MAPK)

Mitogen activated protein kinases are a family of structurallyrelated serine/threonine protein kinases that coordinate variousextra cellular signals to regulate cell growth and survival (Changand Karin, 2001; Johnson and Lapadat, 2002; Marshall, 1995).Cisplatin has been shown to cause activation of ERK in several celltypes although there are controversies whether activation of ERKprevents or contributes to cisplatin induced cell death (Tang et al.,2010; Wang et al., 2000; Yeh et al., 2002; Nowak, 2002; Hayakawaet 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 directlyphosphorylates p53 causing up regulation of p21, 45kd-growtharrest and DNA damage (GADD45), and mouse double minute2 homolog (Mdm2) (DeHaan et al., 2001).Thus, activation of ERKmay 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 isactivated by various stress stimuli, including DNA damage. Both cisand trans forms of cisplatin activate the JNK pathway. p73, aproapoptotic member of p53 forms a complex with JNK leads tocisplatin 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 alreadybeen identied that EGFR as a substrate for p38 MAPK andcisplatin-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 p53and stimulates the transcription of proapoptotic genes PUMA andNOXA to induce apoptosis (Cuadrado et al., 2007). Therefore, thep38 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 actdownstream of phosphoinositide 3-kinase (P13K) and plays acritical role in the cell survival (Brazil and Hemmings, 2001).It has been demonstrated that cisplatin-induced DNA damagecaused phosphorylation of BAD at ser136 via Akt (Hayakawaet al., 2000). Basically, BAD is phosphorylated in cells with


cisplatin- induced DNA damage and this BAD phosphorylation isrequired for cell viability after cisplatin treatment in both cisplatinresistant and -sensitive cells. Previous study showed that cisplatin-induced DNA damage triggers the phosphorylation of both BADSer-112 via an ERK cascade and BAD Ser-136 via a PI-3 K-PKB/Aktcascade (Hayakawa et al., 2004). Iinhibition of either of thesecascades sensitizes ovarian cancer cells to cisplatin (Hayakawaet al., 2000; Ohta et al., 2006).

It has been demonstrated that cisplatin-induced phosphoryla-tion of BAD Ser-112 is MEK-dependent; while cisplatin-inducedphosphorylation of BAD Ser- 136 is PI-3K-Akt-dependent. Inaddition, cisplatin induced phosphorylation of both BAD Ser-112and Ser-136 is involved in maintaining cell viability after cisplatintreatment. All these results suggest that the ERK and PI-3K-Aktsignaling cascades converge at BAD to suppress the apoptoticeffect of BAD (Hayakawa et al., 2000).

5.9. Cisplatin and signaling for DNA damage

Mutations are caused by several signals associated with stress.DNA once is damaged is followed by activation of cell cycle checkpoints, there by delaying the cell cycle progression either to repairor to permanently eliminate the cells by inducing cell death. Theresponse of cells to cisplatin induced DNA damage will decide thefate of a cell to live or die (Basu and Krishnamurthy, 2010).

5.10. p53 and DNA damage response to cisplatin treatment

p53 is a short lived protein, which is activated (phosphoryla-tion) by Ataxia telangiectasia mutated (ATM) on DNA damagesignal. The activated p53 now in turn activates Mdm2, which is E3ubiquitin ligase. p53 can transactivate genes involved in cell cycleprogression, DNA repair and apoptosis. p53 can regulate cisplatininduced cell death by several mechanisms like: degradation ofice-like inhibitory protein (FLIP), direct binding and counter-acting the antiapoptotic function of B-cell lymphoma-extra-large(Bcl-xL), over expression of phosphatase and tensin homolog(PTEN) and inhibition of AMPK (Basu and Krishnamurthy, 2010).Although p53 plays an important role in cisplatin induced DNAdamage response, p53 negative cells also respond to cisplatininduced DNA damage. This suggests the existence of alternatepathway for this event to occur upon stress.

5.11. Cyclobutanedicarboxylate (c-abl) and DNA damage responseto cisplatin treatment

c-Abl is tyrosine kinase receptor and contains nuclear localiza-tion motifs and nuclear export signals. Upon DNA damage, c-Abl isrecruited from cytoplasm to nucleus, later associate with andphosphorylates MEK kinase 1. This complex activates jun amino-terminal kinase /stress-activated protein kinases (JNK/SAPK)(Kharbanda et al., 2000). It is also demonstrated that activationof c-Abl and JNK is conditional upon the recognition of cisplatininduced DNA damage by the mismatch repair (MMR) system sincec-Abl response is absent in MMR-decient cells (Nehme et al.,1999).

The MMR/c-Abl binds to p73, a member of p53 family to startapoptosis (Gong et al., 1999). Phosphorylation and stabilization ofp73 can increase its proapoptotic function by disassociating fromp63, another p53 family member (Basu and Krishnamurthy, 2010).C-Jun will enhance the p73 stability by binding to transcription coactivator Yap1, preventing proteasomal degradation of p73 andresults in the recruitment of p300 to trigger transcription ofproapoptotic genes (Levy et al., 2008).Cisplatin can trigger clea-vage of c-Abl which is a substrate for caspase and proteolytic

cleavage of c-Abl was shown to be important for cisplatin-inducedapoptosis (Machuy et al., 2004).

5.12. Cisplatin modulation of gene expression

In vitro studies suggest that cisplatin resistance can result fromepigenetic changes at the molecular and cellular levels, includingreduced accumulation of the platinum compounds by either activeefux/sequestration/secretion or impaired inux, detoxicationby GSH conjugates, metallothioneins and other antioxidants,increased levels of DNA damage repair (nucleotide excision repairand mismatch repair), changes in DNA methylation status, altera-tions of membrane protein trafcking as a result of defectiveorganization and distribution of the cytoskeleton, overexpressionof chaperones, up- or down-regulated expression of microRNA(miRNA1), transcription factors and small GTPases, inactivation(Shen et al., 2012).

As a consequence of reduced uptake or retention, the formationof platinum-DNA adducts is correspondingly decreased, reducingcytotoxicity, resulting in more resistance to the platinum com-pound. Signicant reductions in platinum-DNA adduct formation(9-fold) and ribosomal RNA gene-specic interstrand cross-link formation (12-fold) have been reported in studies withhuman hepatoma cisplatin-resistant 7404-CP20 cells. Howeverthe removal rates of the total platinum-DNA adducts and gene-specic interstrand cross-links were similar to those in theirparental 7404 cells (Johnson et al., 1996).

Cisplatin also induces endoplasmic reticulum stress andnucleus-independent apoptotic signaling (Mandic et al., 2003).Because cisplatin is a DNA-damaging agent and an inducer ofapoptosis, it is reasonable to expect changes in HSPs in thedevelopment of cellular resistance to the drug. HSP60 was sig-nicantly expressed in both human cervical and liver carcinoma(Shen et al., 2012). Up-regulation of HSP27, HSP70, HSP72, GRP78,and HSP90 have been reported to be involved in CP-r ovariancancer (Arts et al., 1999; Liu et al., 2002), breast cancer (Vargas-Roig et al., 1998), colon cancer (Bel et al., 1999), cervical HeLacells (Huang et al., 2000) and laryngeal carcinoma cells (Brozovicet al., 2001).

The low molecular weight GTP-binding proteins of the Rhofamily, including RhoA, RhoB, RhoC, and Rac, all belong to the Rastumor suppressor gene family. Reduced expression of smallGTPases such as Rab5, Rac1, and RhoA was detected in humancisplatin-resistant cells in association with decreased accumula-tion of radiolabeled compounds (Shen et al., 2004). The ribosomalprotein L36 was found to present cisplatin resistance in humancarcinoma cells (Shen et al., 2006). In human breast cancer MCF-7cells, reduced expression of the ribosomal protein P0 was found byproteomic analysis (Smith et al., 2007). Moreover, ectopic L37 overexpression can attenuate the DNA damage response mediated byp53 (Llanos and Serrano, 2010).

It has been reported that transcription factors such as Y-boxbinding protein-1, CCAAT-binding transcription factor 2, activatingtranscription factor 4, zinc nger factor 143, the nuclear transcrip-tion factor- B, the microphthalmia-associated transcription factor,the forkhead transcription factor O, and mitochondrial transcrip-tion factor A, play a major role in cisplatin resistance (Shen et al.,2012). It was rst found that the levels of nuclear factor (Erythroid-Derived 2)-like 2 (Nrf2) expression in Nrf2-decient murineembryonic cells and human ovarian cancer SK-OV cisplatin-resis-tant cells correlate with the extent of resistance to cisplatin. Loss ofNrf2 or inhibition by siRNA resulted in increased cell death,cytotoxicity, and apoptosis in response to cisplatin treatmentcompared with control cells (Cho et al., 2008). Also, increasedexpression in GCF2-transfected KB-3-1 cells results in reducedRhoA expression, disruption of actin-lamin dynamics,


mislocalization of the membrane protein MRP1, and reduction incisplatin accumulation, leading to 3-fold resistance to cisplatin(Shen et al., 2012).

5.13. Computational studies of cisplatin

Cisplatin is one of the most effective anticancer drugs currentlyin use. Following the nding of its antitumor activity over threedecades ago, strong research has been carried out to reveal thedetails of its cytotoxic activity and to design analogs with reducedside effects (Mantri and Baik, 2006). Recently, computationalstudies have been conducted to complement experimental works.The hydrolysis process of cisplatin which activates the drug wasthe goal of past research. cisplatinDNA interactions are the nexttheoretical studies, since DNA is the primary target of the drug.At present, to study the thermodynamics and kinetics of not onlycisplatinDNA complexes, but also of other complexes such as Pt(II)-based cisplatin analogs, other transition metal complexes, andDNA binding organic molecules, both quantum mechanical andmolecular mechanical methods are being used. Future research isaiming at elucidating the role of repair enzymes in modulating thecytotoxic activity of DNA binding agents (Mantri and Baik, 2006).

The combination of dramatically improved computer hardwareand robust, sophisticated, and numerically efcient modeling softwarehas allowed for employing high levels of theory to examine variousaspects of cisplatin chemistry using computational chemistry techni-ques. The very rst computational studies on cisplatin aimed at betterunderstanding the hydrolysis of cisplatin, because the activation byhydrolysis had long been established as the rate-limiting step (Baschet al., 1986). An intriguing question had been the preferentialantitumor activity of the cis isomer over the trans isomer, a fact thenattributed to the steric effects of binding DNA bases. It was eventuallydiscovered that the cis orientation of the leaving groups allowedbinding of two adjacent guanine bases on the same strand, whichresulted in a large kink in the DNA helix, causing polymerases to bestalled at the kink. However, it was demonstrated that the transisomer is favored over the cis isomer in all cases due to reduction inligandligand repulsion, especially in the case of anionic ligands. Thesedifferences become negligibly small when favorable hydrogen bondinginteractions are possible between the ammine ligands and the otherlabile ligands (Basch et al., 1986).

There is increasing awareness now that one important reasonfor cisplatin's performance is associated to the high mobility group(HMG) proteins that bind to DNA and protect the drugDNAadducts against excision repair (Wang and Lippard, 2005). Toenable comparison of the binding of Pt(II) to various positions inthe four nucleobases in DNA and to keep computational costs to aminimum, Pt(NH3)32 was used as the fragment that interactedwith the bases. The ranking of the bases followed the order: G(N7)4C(N3)4C(O2)4G(O6)4A(N3)EA(N1)4A(N7)4G(N3)4T(O4)4T(O2), based on differential Pt(II) binding energies. On the basis ofthe ranking above and the fact that most of the potential bindingsites are in reality unavailable for binding due to WatsonCrickbase pairing, the N7 position of guaninein particular intrastrandbinding to two adjacent guanineswas conrmed as the preferredbinding site, in full agreement with experimental evidence (Mantriand Baik, 2006)

Density functional theory was applied to provide new insightsinto the structure and reactivity of cis- and transplatin and relatedhydrolysis product (Carloni et al., 2000) and also to compare theelectronic structures of cisplatin and its second-generation analogcarboplatin (Carloni and Andreoni, 1996). Results suggested thatthe replacement of the chloride ligands of cisplatin by carboxylateligands in carboplatin resulted in a greater stability of the metal-ligand bonds in the latter, leading to potentially higher activationenergy for substitution reactions. Later, a more comprehensive

study comparing the geometric, electronic, and vibrational proper-ties of cisplatin using different basis sets, including pure ECP andhybrid ECP with various electron correlation methods up to theMP4 level, and DFT, was performed (Pavankumar et al., 1999).

Thermodynamics of hydrolysis of cisplatin and bis(ethylene-diamine) dichloroplatinum(II) using a combination of molecularmechanics for obtaining optimized geometries of the reactantsand products, and the extended Huckel method for derivingcharge distributions and electronic energies were studied. Thishydrolysis was studied by several others using various levels oftheory, where a common approach adopted has been to use DFTto optimize the geometries of the key intermediates andreevaluate their energies using higher level ab initio methods,and/or adding solvation corrections based on continuum dielec-tric models. describes the interaction of transplatin and thefragments trans-PtCl2(NH3) and Pt(NH3)32 with G:C and A:Tbase 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 muchgreater preference over adenine, which is somewhat surprisingbecause it could be argued that the inductive effects of theelectron-withdrawing oxo group at the C6 position of guanineshould reduce the electron density at N7 compared to adeninethat has an electron-donating amino group at the C6 position,thus making the N7 of guanine less nucleophilic compared toadenine (Mantri and Baik, 2006). The major difference betweenguanine and adenine is that N1 of guanine is protonated, whileadenine exposes an N1 lone pair. The presence of the N1 protondiminishes the delocalization of electron density over thenitrogen lone pairs of the purine skeleton resulting in greaterlocalization of electron density on the N3 and N7 atoms ofguanine, compared to adenine where the electron density isdelocalized over the N1, N3, and N7 atoms (Mantri and Baik,2006). In an attempt to identify yet another subtle electronicfeature that could help in distinguishing between the reactivityof adenine and guanine, it was discovered that the [Pt] fragmentis a poor -donor; thus -back donation does not appear to playa major role (Mantri and Baik, 2006).

Cisplatin binds to other cellular components, resulting in eitherdeactivation of the drug and/or disruption of normal biochemicalpathways. Thus, signicant efforts have focused on understandingthe binding of cisplatin with other entities found in the cells; inparticular S- and N-containing ligands that are expected have thegreatest afnity for platinum based on good hardness- softnessmatching. It was reported a thorough DFT study which comparedthe PtL bond strengths of a series of tri- ammine platinum(II)complexes with oxygen-, nitrogen- and sulfur-donor ligands asmodels of competing ligands encountered in a biological system(Deubel, 2002). In another study, the kinetics of the substitutionreaction of various nitrogen- and sulfur ligands with the activatedcisplatin complex was modeled using DFT. This study revealed thatkinetically N-donor ligands were preferred over S-donors, with theselectivity originating from electrostatic rather than orbital-basedinteraction (Deubel, 2004).

Other areas of active study on cisplatin are degree of localbending/unwinding upon cisplatin binding, the disruption of basestacking and other local distortions, the thermodynamics of thevarious 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 thebinding and recognition of HMG domain and/or DNA repairproteins to these adducts (Mantri and Baik, 2006). Computationalmodels have made signicant contributions to understanding thenature and reactivity of cisplatin and allowed for delineating manyfeatures of how it binds to DNA.


6. Toxicological effects of cisplatin

Cisplatin interacts with DNA, and forms covalent adduct withpurine DNA bases and this platinum compound, interaction is theroot cause for cytotoxic effect of cisplatin (Yousef et al., 2009).Cisplatin treatment has been associated with several toxic sideeffects including nephrotoxicity (de Jongh et al., 2003), hepato-toxicity and Cardiotoxicity (Al-Majed, 2007). Many cardiac eventshave been reported in many case reports including electro-cardiographicchanges, arrhythmias, myocarditis, cardiomyopathyand congestive heart failure (Yousef et al., 2009). Decreasein antioxidant defense system is reported due to oxidative stressthrough the generation of reactive oxygen species, includingantioxidant enzymes and non enzymatic molecules, reducedglutathione, are major alterations in the cisplatin toxicity (Kartet al., 2010).

6.1. Hepatotoxicity

High dosage of cisplatin may lead to hepatotoxicity (dos Santoset al., 2007).Oxidative stress is the main reason for cisplatin-induced toxicity possibly due to depletion of reduced glutathioneGSH (Yilmaz et al., 2004), also many studies reported that therewere a signicant elevation in the hepatic malonaldehyde (MDA)and reduction in the level of antioxidant enzymes in rats treatedwith cisplatin (Yilmaz, et al., 2005; Mansour et al., 2006). The mostsensitive biomarkers directly concerned in causing the cellulardamage and toxicity are transaminases, because they are cyto-plasmic in location and are released into the circulation aftercellular damage. Elevation of the hepatic enzymes level in serumand bilirubin are the indicators for impaired liver functions (Iseriet al., 2007). Cisplatin hepatotoxicity was shown to be exacerbatedby increased expression of cytochrome P450-2E1 enzyme (Caroand Cederbaum, 2004).Observed histopathological changes will benecrosis and degeneration of hepatocytes with inammatory cellsinltration around portal area with sinusoidal dilatation (Kartet al., 2010; Cetin et al., 2006). Recent studies have focused onmethods for protection of cisplatin-induced Hepatotoxicity usingvarious agents, such as selenium (Liao et al., 2008) and vitamin E(Naziroglu et al., 2004; Iraz et al., 2005).

6.2. Cardiotoxicity

Leakage of lactate dehydrogenase (LDH) and creatine kinase(CK) from cardiac myocytes is due to cardiotoxicity could be asecondary event following cisplatin-induced lipid peroxidation ofcardiac membranes. Degeneration and necrosis of cardiac muscleber cells with brous tissue reaction and vacuolated cytoplasm ofmany muscle cells and blood vessels are inated with blood arethe histological changes of cisplatin induced toxicology (Al-Majedet al., 2006).

6.3. Nephrotoxicity

The kidney accumulates cisplatin to a greater degree than otherorgans and is the major route for its excretion. The cisplatinconcentration in proximal tubular epithelial cells is about 5 timesthe serum concentration (Kuhlmann et al., 1997).The dispropor-tionate accumulation of cisplatin in kidney tissue contributes tocisplatin-induced nephrotoxicity (Arany and Sarstein, 2003).

Biosynthesis of amino acid lysine and methionine yields a qua-ternary ammonium compound called Carnitine, which is required forthe transport of fatty acids from the cytosol into the mitochondriaduring the breakdown of lipids to generate metabolic energy. Kidneydamage is caused by the inhibition of Carnitine synthesis and also by

the Carnitine reabsorption by the proximal tubule of nephron, whichis due to declined production of Carnitine.

Cisplatin is cleared by the kidney by both glomerular ltrationand tubular secretion (Yao et al., 2007; Ishida et al., 2002).Cisplatin concentrations within the kidney exceed those in bloodsuggesting an active accumulation of drug by renal parenchymalcells. Studies in recent years have identied two different mem-brane transporters capable of transporting cisplatin into cells: Ctr1and OCT2 (Ishida et al., 2002). Later, cisplatin is biotransformed inthe kidney into cysteinyl glycine conjugates and other high thiolsby some localized enzymes.

6.4. Other organ toxicity

Other cisplatin-induced organ toxicities such as ototoxicity,gastrotoxicity, myelosuppression, allergic reactions and somereproductive toxic effects have also been reported (Hartmannet al., 2000; Hartmann and Lipp, 2003)

7. Conclusions

Cisplatin is one of the most effective anticancer agents widelyused in the treatment of solid tumors. It has been extensively usedfor the cure of different types of neoplasms including head andneck, lung, ovarian, leukemia, breast, brain, kidney and testicularcancers. In general, cisplatin and other platinum-based com-pounds are considered as cytotoxic drugs which kill cancer cellsby damaging DNA, inhibiting DNA synthesis and mitosis, andinducing apoptotic cell death. Several molecular mechanisms ofaction including induction of oxidative stress as characterized byreactive oxygen species production and lipid peroxidation, induc-tion of p53 signaling and cell cycle arrest, down-regulation ofproto-oncogenes and anti-apoptotic proteins, and activation ofboth intrinsic and extrinsic pathways of apoptosis. However,cisplatin chemotherapy is also associated with substantial sideeffects that include hepatotoxic, nephrotoxic, cardiotoxic, neuro-toxic and/or hematotoxic damage. Also, some patients may relapsefrom cisplatin treatment with their cancers being refractory tocisplatin regimen. Hence, combination therapies of cisplatin withother drugs are common practice in the treatment of humancancers. Findings of several studies have suggested that othercompounds combined with cisplatin constitute the best therapeu-tic approach to overcome drug resistance and reduce the undesir-able side effects. Moving forward, combinatorial strategies whichtarget multiple mechanisms, such as reducing cisplatin uptake andreducing inammation, may offer the best chance for clinicallymeaningful prevention.

Acknowledgments

The research described in this publication was made possibleby a grant from the National Institutes of Health (Grant no.G12MD007581) through the RCMI Center for EnvironmentalHealth at Jackson State University.

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