3.2. Cisplatin and Ovarian Cancer

Ovarian cancer has the highest mortality among gynecologic cancers. Most patients with ovarian cancer are diagnosed at late stages due to lack of effective screening strategies and specific symptoms associated with early-stage disease. Conventional treatment for late stages of ovarian cancers is surgical excision followed by platinum/ taxane combination chemotherapy. Although this treatment regime is effective as the first-line treatment, recurrence occurs in up to 75% of ovarian cancer patients. Patients with recurrent ovarian cancer ultimately develop resistance to chemotherapy and eventually succumb to the disease (Agarwal and Kaye, 2003). About 90% of ovarian cancers arise originally from ovaries with an unknown reason, while the remainder has hereditary background, or are associated with breast and colon cancers (Lynch, Casey et al., 2009). Cisplatin derivatives are used as the mainline treatment of ovarian cancer, despite their severe side effects and development of resistance. Cisplatin is used in combination with other chemical agents or compounds to treat ovarian cancer in both the resistant and sensitive cell lines. For example Cisplatin is used along with honey venom (Alizadehnohi, Nabiuni et al., 2012), withaferin (Kakar, Jala et al., 2012), trichostatin A or 5-aza-2′-deoxycytidine (Meng, Sun et al., 2013), overcoming chemotherapy resistance of ovarian cancer cells by liposomal Cisplatin (Koch, Krieger et al., 2013)

3.3. Cisplatin and Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common malignant disease with more than 600,000 new cases registered worldwide every year (Parkin, Bray et al., 2005). Despite improved treatment 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 last decades. Cisplatin alone is not an effective drug in treating the disease. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, doxorubicin, and or gemcitabine in patients with metastatic urothelial carcinoma has been reported (Scher, 1992;Matsuki, Takahashi et al., 2013).

3.4. Cisplatin and Breast Cancer

Breast cancer is one of the leading causes of women mortality worldwide. Chemotherapy is the only option for treating the malignant breast cancer and condition for increases the lifespan of the patient (Decatris, Sundar et al., 2004). Chemotherapeutic agents have been developed to counter the continuing breast cancer problem. However, most chemotherapeutic drugs effectively target rapidly dividing cells causing damage and are thus referred to as “cytotoxic drugs.” Cisplatin is an important chemotherapeutic agent used widely or the treatment of a variety of malignancies, including breast, testicular, ovarian, cervical, prostate, head and neck, bladder, lung and refractory non-Hodgkin's lymphomas (Tsimberidou, Braiteh et al., 2009;Dhar, Kolishetti et al., 2011). The cytotoxic effect is likely a result of inhibition of replication by cisplatin-DNA adducts and induction of apoptosis (Siddik, 2003).

4.1.Cisplatin and Paclitaxel

Paclitaxel is a mitotic agent that binds preferentially to microtubules(Parness and Horwitz, 1981) and the resulting stabilization of microtubules inhibits the reorganization of the microtubule network. Paclitaxel has been demonstrated to be active against previously treated ovarian carcinoma (Sarosy, Kohn et al., 1992; McGuire, Rowinsky et al., 1989; Einzig, Wiernik et al., 1992),breast carcinoma (Holmes, Walters et al., 1991), lung carcinoma (Murphy, Fossella et al., 1993), and melanoma (Legha, Ring et al., 1990;Einzig, Hochster et al., 1991) as well as for head and neck carcinoma (Forastiere, 1994). The combination chemotherapy with paclitaxel, cisplatin and fluorouracil is an active and tolerable as first-line and second line therapy in Chinese patients with advanced gastric and esophagogastric junction adenocarcinoma which showed a better tolerance has also been reported (Kim, Shin et al., 1999)

4.2. Cisplatin and Tegafur-uracil (UFT)

UFT is an oral anticancer agent comprised of tegafur and uracil in a 1:4 fixed molar ratio and is absorbed very well from the small intestine (Fujii, Kitano et al., 1979).Combination chemotherapy comprised of oral UFT (a combination of tegafur and uracil) and cisplatin was shown to be an effective regimen for the treatment of advanced non-small cell lung carcinoma (Ichinose, Yosimori et al., 2000).

4.3. Cisplatin and Doxorubicin

The combination of doxorubicin and cisplatin is effective and well tolerated. It might be considered for palliation of symptomatic patients with diffuse malignant pleural mesothelioma DMPM (Ardizzoni, Rosso et al., 1991). Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin showed encouraging results (Dreyfuss, Clark et al., 1987).

4.4. Cisplatin and Gemcitabine

As compared with gemcitabine alone, cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer (Valle, Wasan et al., 2010).

4.5. Cisplatin and Vitamin D

Vitamin D and its analogs regulate gene expression by binding to specific vitamin D receptors (VDR). Upon ligand activation and dimerization with retinoid X receptor (RXR), VDR – RXR heterodimers bind specific nucleotide sequences, vitamin D response elements (VDREs), in target genes to activate or repress their expression (Baniahmad and Tsai, 1993). A number of vitamin D target genes have been identified 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, Banwell et al., 2006;Nagpal, Na et al., 2005).

Cisplatin is used along with vitamin D in treating squamous cell carcinoma (Light, Yu et al., 1997) and colon cancer (Milczarek, Rosinska et al., 2013). Published research has shown that pre-treatment for 72 hours of human promyelocytic leukemia (HL-60)cells with calcitriol or its new analogues significantly potentiated their sensitivity to the antiproliferative effect in vitro of cisplatin, doxorubicin or genistein. Moreover, for all cytotoxic agents tested a synergistic antiproliferative effect was observed. This effect was expressed as a significant decrease of the ID50 (inhibitory dose 50%) values for each cytotoxic agent applied after pretreatment of HL-60 cells with calcitriol or its analogues in comparison with the effect of cytotoxic agent applied alone (Siwinska, Opolski et al., 2001).

5.1.Cisplatin-Induced Oxidative Stress

Under normal physiological conditions, cells control reactive oxygen species levels by balancing the generation of reactive oxygen species with their elimination by scavenging system (reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT). But under oxidative stress conditions, excessive reactive oxygen species can damage cellular proteins, lipids and DNA, leading to fatal lesions in cells that contribute to carcinogenesis. Cancer cells exhibit greater reactive oxygen species stress than normal cells do, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial malfunction. Oxidative stress is the one of most important mechanisms involved in cisplatin toxicity. The mitochondrion is the primary target for cisplatin induced oxidative stress, resulting in loss of mitochondrial protein sulfhydrl group, calcium uptake inhibition and reduction of mitochondrial membrane potential (Saad, Najjar et al., 2004)

Exposure to oxidative stress can upset regular biological functions. Cisplatin also induces reactive oxygen species that trigger cell death besides DNA damage. Cell death occurs upon immediate activation of numerous signaling pathways, whereas the definite pathways depend on the (cancer) cell. The formation of reactive oxygen species depends on the concentration of cis-diamminedichloro platinum(II) and the length of exposure (Brozovic, Ambriovic-Ristov et al., 2010). The intracellular redox homeostasis is maintained by the thiol group (-SH) containing molecules. Under certain conditions a thiol group may lead to formation of thiyl radicals that in turn can interact with molecular oxygen, therefore generating reactive oxygen species (Desoize, 2002).

Excessive reactive oxygen species can induce apoptosis through both the extrinsic and intrinsic pathways (Ozben, 2007). In the extrinsic pathway of apoptosis, reactive oxygen species are generated by Fas ligand as an upstream event for Fas activation via phosphorylation, which is necessary for subsequent recruitment of Fas-associated protein with death domain and caspase 8 as well as apoptosis induction(Gupta, Hevia et al., 2012). In the intrinsic pathway, reactive oxygen species function to facilitate cytochrome c release by activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well as inhibiting 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 in both apoptosis and necrosis in cancer cells(Hampton and Orrenius, 1997). Reactive oxygen species can also induce cell death through autophagy, which is a self-catabolic process involving sequestration of cytoplasmic contents (exhausted organelles and protein aggregates), for degradation in lyposomes (Shrivastava, Kuzontkoski et 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 species including monoaqua [cis-(NH) PtCI(HO)]⁺ and diaquated [cis-(NH)Pt(HO)]²⁺ forms (Jennerwein and Andrews, 1995; Aggarwal, Broomhead et al., 1980). These hydrolyzed forms of cisplatin have been shown to be 1,000 times more reactive than normal cisplatin, and act through the inhibition of mitochondrial respiration by uncoupling oxidative phosphorylation (Aggarwal, 1993). This result in an efflux of calcium from the mitochondria and a temporary increase in the cellular calcium levels, which is thought to play a significant role in the disruption of normal calcium homeostasis, and hence cell function.

Mitochondrial glutathione (GSH) seems to be essential in the regulation of inner mitochondrial permeability and enzyme function by keeping SH in the reduced state. When the SH-groups of enzymes are not maintained in a reduced form, they become inactivated. Cisplatin induced toxicities, especially nephrotoxicity, seem to be related to a decrease in the intracellular concentrations of GSH and protein bound SH-groups. Nicotinamide adenine dinucleotide (NADH), which helps to maintain SH groups, declines with cisplatin treatment. Consequently, this depletion of GSH and NADH appears to result in the inhibition of some dehydrogenases, resulting in the uncoupling of oxidative phosphorylation leading to hydroxyl radical formation and oxidative stress. These free radicals attack polyunsaturated lipids and proteins and initiate lipid per oxidation. This process becomes autolytic and causes severe damage to membrane integrity (Aggarwal, 1998).

In summary, cisplatin's disruption of calcium homeostasis initiates primary events such as lipid per oxidation and enzyme inhibition. These events damage the cells through mitochondrial damage, inhibition of mitochondrial function, depletion of adenosine triphosphate (ATP) and other cofactors. This probably leads to apoptosis and tissue necrosis. Thus, it seems that elevated calcium levels, via calcium supplementation, may act as another means of cytoprotection, by competing for binding sites with cisplatin and prevent 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 activation of a family of cysteine proteases called caspases (Salvesen and Dixit, 1997;Cummings, Lasker et al., 2000). Caspase activation is the key step in the beginning of apoptosis, and several stimuli activate caspases, including those that activate plasma membrane death receptors (caspase 8) and cause mitochondrial dysfunction (caspase 9). Caspases are either initiators or executioners of apoptosis. Initiator caspases include caspases 8 and 9, and activation of these caspases results in activation of downstream or executioner caspases such as caspases 3 and 7 (Salvesen and Abrams, 2004). Executioner caspases are accountable for many of the biochemical characteristics of apoptosis, including cleavage and activation of poly (ADP-ribose) polymerase and of the inhibitor of caspase activator domain protein, which leads to DNA fragmentation.

Cisplatin primarily induces cell death by apoptosis and a defect in apoptotic signaling could also confer cisplatin resistance. There are two major pathways of apoptotic cell death (Nunez, Benedict et al., 1998;Kischkel, Hellbardt et al., 1995). The extrinsic pathway is initiated when ligands bind to the tumor necrosis factor-α (TNFα) receptor super family followed by oligomerization and recruitment of procaspase-8 via adaptor molecules to form the death-inducing signaling complex (DISC). The intrinsic pathway is initiated by cellular stress, such as DNA damage, resulting in release of cytochrome-c from the mitochondria causing activation of procaspase-9 through the interaction with apoptosis promoting activating factor-1 (APAF-1) and formation of an active apoptosome complex. Bcl-2 family proteins regulate DNA damage-induced apoptosis by 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, Andrews et al., 1990;Hirata, Kikuchi 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, Zhou et al., 2010;Wang, Martindale et al., 2000;Yeh, Chuang et al., 2002;Nowak, 2002;Hayakawa, Ohmichi et al., 1999;Persons, Yazlovitskaya et al., 1999;Basu and Tu, 2005). Cisplatin-induced extracellular-signal-regulated kinase (ERK) activation precedes 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, Yazlovitskaya 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, Dickman 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 identified that EGFR as a substrate for p38 MAPK and cisplatin-induced receptor internalization was triggered by p38-mediated phosphorylation of the receptor (Winograd-Katz and Levitzki, 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, Lafarga 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, Ohmichi et al., 2000). Basically, BAD is phosphorylated in cells with cisplatin- induced DNA damage and this BAD phosphorylation is required for cell viability after cisplatin treatment in both cisplatin resistant and -sensitive cells. Previous study showed that cisplatin-induced DNA damage triggers the phosphorylation of both BAD Ser-112 via an ERK cascade and BAD Ser-136 via a PI-3K-PKB/Akt cascade. Iinhibition of either of these cascades sensitizes ovarian cancer cells to cisplatin (Hayakawa, Ohmichi et al., 2000).

It has been demonstrated that cisplatin-induced phosphorylation of BAD Ser-112 is MEK-dependent; while cisplatin-induced phosphorylation of BAD Ser- 136 is PI-3K-Akt-dependent. In addition, cisplatin induced phosphorylation of both BAD Ser-112 and Ser-136 is involved in maintaining cell viability after cisplatin treatment. All these results suggest that the ERK and PI-3K-Akt signaling cascades converge at BAD to suppress the apoptotic effect of BAD (Hayakawa, Ohmichi 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 check points, there by delaying the cell cycle progression either to repair or to permanently eliminate the cells by inducing cell death. The response of cells to cisplatin induced DNA damage will decide the fate 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 (phosphorylation) by Ataxia telangiectasia mutated (ATM) on DNA damage signal. The activated p53 now in turn activates Mdm2, which is E3 ubiquitin ligase. p53 can transactivate genes involved in cell cycle progression, DNA repair and apoptosis.p53 can regulate cisplatin induced cell death by several mechanisms like: Degradation of flice-like inhibitory protein (FLIP), direct binding and counteracting 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 DNA damage response, p53 negative cells also respond to Cisplatin induced DNA damage. This suggests the existence of alternate pathway for this event to occur upon stress.

5.11.Cyclobutanedicarboxylate (c-Abl) and DNA Damage Response to Cisplatin Treatment

c-Abl is tyrosine kinase receptor and contains nuclear localization motifs and nuclear export signals. Upon DNA damage, c-Abl is recruited from cytoplasm to nucleus, later associate with and phosphorylates MEK kinase 1. This complex activates jun amino-terminal kinase /stress-activated protein kinases (JNK/SAPK) (Kharbanda, Pandey et al., 2000). It is also demonstrated that activation of c-Abl and JNK is conditional upon the recognition of cisplatin induced DNA damage by the mismatch repair (MMR) system since c-Abl response is absent in MMR-deficient cells (Nehme, Baskaran et al., 1999).

The MMR/c-Abl binds to p73, a member of p53 family to start apoptosis (Gong, Costanzo et al., 1999). Phosphorylation and stabilization of p73 can increase its proapoptotic function by disassociating from p63, another p53 family member (Basu and Krishnamurthy, 2010). C-Jun will enhance the p73 stability by binding to transcription co activator Yap1, preventing proteasomal degradation of p73 and results in the recruitment of p300 to trigger transcription of proapoptotic genes (Levy, Adamovich et al., 2008).Cisplatin can trigger cleavage of c-Abl which is a substrate for caspase and proteolytic cleavage of c-Abl was shown to be important for cisplatin-induced apoptosis (Machuy, Rajalingam et al., 2004).

5.12. Cisplatin Modulation of Gene expression

In vitro studies suggest that cisplatin resistance can result from epigenetic changes at the molecular and cellular levels, including reduced accumulation of the platinum compounds by either active efflux/sequestration/secretion or impaired influx, detoxification by GSH conjugates, metallothioneins and other antioxidants, increased levels of DNA damage repair (nucleotide excision repair and mismatch repair), changes in DNA methylation status, alterations of membrane protein trafficking as a result of defective organization and distribution of the cytoskeleton, overexpression of chaperones, up- or down-regulated expression of microRNA (miRNA1), transcription factors and small GTPases, inactivation (Shen, Pouliot et al., 2012).

As a consequence of reduced uptake or retention, the formation of platinum-DNA adducts is correspondingly decreased, reducing cytotoxicity, resulting in more resistance to the platinum compound. Significant reductions in platinum-DNA adduct formation (9-fold) and ribosomal RNA gene-specific interstrand cross-link formation (12-fold) have been reported in studies with human hepatoma cisplatin-resistant 7404-CP20 cells. However the removal rates of the total platinum-DNA adducts and gene-specific interstrand cross-links were similar to those in their parental 7404 cells (Johnson et al., 1996).

Cisplatin also induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling (Mandic, Hansson et al., 2003). Because cisplatin is a DNA-damaging agent and an inducer of apoptosis, it is reasonable to expect changes in HSPs in the development of cellular resistance to the drug. HSP60 was significantly expressed in both human cervical and liver carcinoma (Shen, Pouliot, Hall, and Gottesman, 2012). Up-regulation of HSP27, HSP70, HSP72, GRP78, and HSP90 have been reported to be involved in CP-r ovarian cancer (Arts, Hollema et al., 1999;Liu, Opipari et al., 2002), breast cancer (Vargas-Roig, Gago et al., 1998), colon cancer (Belfi, Chatterjee et al., 1999), cervical HeLa cells (Huang, Ip et al., 2000) and laryngeal carcinoma cells (Brozovic, Simaga et al., 2001).

The low molecular weight GTP-binding proteins of the Rho family, including RhoA, RhoB, RhoC, and Rac, all belong to the Ras tumor suppressor gene family. Reduced expression of small GTPases such as Rab5, Rac1, and RhoA was detected in human cisplatin-resistant cells in association with decreased accumulation of radiolabeled compounds (Shen, Liang et al., 2004). The ribosomal protein L36 was found to present cisplatin resistance in human carcinoma cells (Shen, Liang et al., 2006). In human breast cancer MCF-7 cells, reduced expression of the ribosomal protein P0 was found by proteomic analysis (Smith, Welham et al., 2007). Moreover, ectopic L37 over expression can attenuate the DNA damage response mediated by p53 (Llanos and Serrano, 2010).

It has been reported that transcription factors such as Y-box binding protein-1, CCAAT-binding transcription factor 2, activating transcription factor 4, zinc finger factor 143, the nuclear transcription factor- B, the microphthalmia-associated transcription factor, the forkhead transcription factor O, and mitochondrial transcription factor A, play a major role in cisplatin resistance (Shen, Pouliot, Hall, and Gottesman, 2012). It was first found that the levels of nuclear factor (Erythroid-Derived 2)-like 2 (Nrf2) expression in Nrf2-deficient murine embryonic cells and human ovarian cancer SK-OV cisplatin-resistant cells correlate with the extent of resistance to cisplatin. Loss of Nrf2 or inhibition by siRNA resulted in increased cell death, cytotoxicity, and apoptosis in response to cisplatin treatment compared with control cells (Cho, Manandhar et al., 2008). Also, increased expression in GCF2-transfected KB-3-1 cells results in reduced RhoA expression, disruption of actin-filamin dynamics, mislocalization of the membrane protein MRP1, and reduction in cisplatin accumulation, leading to 3-fold resistance to cisplatin (Shen, Pouliot et al., 2012).

6.1. Hepatotoxicity

High dosage of Cisplatin may lead to hepatotoxicity (dos Santos, Martins et al., 2007).Oxidative stress is the main reason for cisplatin-induced toxicity possibly due to depletion of reduced glutathione GSH (Yilmaz, Iraz et al., 2004), also many studies reported that there were a significant elevation in the hepatic malonaldehyde (MDA) and reduction in the level of antioxidant enzymes in rats treated with cisplatin (Yilmaz, Sogut et al., 2005; Mansour, Hafez et al., 2006).The most sensitive biomarkers directly concerned in causing the cellular damage and toxicity are transaminases, because they are cytoplasmic in location and are released into the circulation after cellular damage . Elevation of the hepatic enzymes level in serum and bilirubin are the indicators for impaired liver functions (Iseri, Ercan et al., 2007). Cisplatin hepatotoxicity was shown to be exacerbated by increased expression of cytochrome P450-2E1 enzyme (Caro and Cederbaum, 2004). Observed histopathological changes will be necrosis and degeneration of hepatocytes with inflammatory cells infiltration around portal area with sinusoidal dilatation (Kart, Cigremis, Karaman, and Ozen, 2010; Cetin, Devrim et al., 2006). Recent studies have focused on methods for protection of cisplatin-induced Hepatotoxicity using various agents, such as selenium (Liao, Lu et al., 2008) and vitamin E (Naziroglu, Karaoglu et al., 2004; Iraz, Kalcioglu et al., 2005).

6.2.Cardiotoxicity

Leakage of lactate dehydrogenase (LDH) and creatine kinase (CK) from cardiac myocytes is due to cardiotoxicity could be a secondary event following cisplatin-induced lipid peroxidation of cardiac membranes. Degeneration and necrosis of cardiac muscle fiber cells with fibrous tissue reaction and vacuolated cytoplasm of many muscle cells and blood vessels are inflated with blood are the histological changes of cisplatin induced toxicology (Al-Majed, Sayed-Ahmed et al., 2006)

6.3.Nephrotoxicity

The kidney accumulates cisplatin to a greater degree than other organs and is the major route for its excretion. The cisplatin concentration in proximal tubular epithelial cells is about 5 times the serum concentration (Kuhlmann, Burkhardt et al., 1997). The disproportionate accumulation of cisplatin in kidney tissue contributes to cisplatin-induced nephrotoxicity (Arany and Safirstein, 2003).

Biosynthesis of amino acid lysine and methionine yields a quaternary ammonium compound called Carnitine, which is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids to generate metabolic energy. Kidney damage is caused by the inhibition of Carnitine synthesis and also by the Carnitine reabsorption by the proximal tubule of nephron, which is due to declined production of Carnitine.

Cisplatin is cleared by the kidney by both glomerular filtration and tubular secretion (Yao, Panichpisal et al., 2007; Ishida, Lee et al., 2002) Cisplatin concentrations within the kidney exceed those in blood suggesting an active accumulation of drug by renal parenchymal cells. Studies in recent years have identified two different membrane transporters capable of transporting cisplatin into cells: Ctr1 and OCT2 (Ishida, Lee et al., 2002). Later, cisplatin is biotransformed in the kidney into cysteinyl glycine conjugates and other high thiols by some localized enzymes.

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