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Article history:
Received 27 March 2014
Received in revised form
13 July 2014
Accepted 14 July 2014
Available online 21 July 2014
Keywords:
Cisplatin
Platinum-based drugs
Mechanisms of action
Cancer treatment
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cisplatin and other platinum-containing drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Uses of cisplatin for cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Cisplatin and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Cisplatin and ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Cisplatin and carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Cisplatin and breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.
Cisplatin and brain cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Combination therapy of cisplatin with other cancer drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Cisplatin and paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Cisplatin and tegafur-uracil (UFT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Cisplatin and doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.
Cisplatin and gemcitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.
Cisplatin and vitamin D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.
Other possible drug combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Molecular mechanisms of cisplatin pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Cisplatin-induced oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Cisplatin modulation of calcium signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Cisplatin-induced cell apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.
Cisplatin and protein kinase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.
Cisplatin and mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.
Cisplatin and jun amino-terminal kinase (JNK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
http://dx.doi.org/10.1016/j.ejphar.2014.07.025
0014-2999/& 2014 Elsevier B.V. All rights reserved.
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5.7.
Cisplatin and p38 mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.
Cisplatin and AKT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.9.
Cisplatin and signaling for DNA damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.10. p53 and DNA damage response to cisplatin treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.11. Cyclobutanedicarboxylate (c-abl) and DNA damage response to cisplatin treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.12. Cisplatin modulation of gene expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.13. Computational studies of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Toxicological effects of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
Cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.
Nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.
Other organ toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Cisplatin (CAS no. 15663-27-1, MF-Cl2H6N2Pt; NCF-119875),
cisplatinum, also called cis-diamminedichloroplatinum(II), is a
metallic (platinum) coordination compound with a square planar
geometry (The chemical book database, 2014). It is a white or deep
yellow to yelloworange crystalline powder at room temperature.
It is slightly soluble in water and soluble in dimethylprimanide
and N,N-dimethylformamide. Cisplatin is stable under normal
temperatures and pressures, but may transform slowly over time
to the trans-isomer (IARC, 1981; Akron, 2009). Cisplatin has a
molecular weight of 301.1 g/mol, a density of 3.74 g/cm3, a melting
point 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 its
chemical structure was rst elucidated by Alfred Werner in 1893.
However, the compound did not gain scientic investigations until
the 1960s when the initial observations of Rosenberg et al. (1965)
at Michigan State University pointed out that certain electrolysis
products of platinum mesh electrodes were capable of inhibiting
cell division in Escherichia coli created much interest in the
possible use of these products in cancer chemotherapy. Since the
identication of cis-dichlorodiammineplatinum (II) (cisplatin, r) as
the agent responsible for this activity, considerable interest has
been 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 shown
anticancer activity in a variety of tumors including cancers of the
ovaries, testes, and solid tumors of the head and neck. It was
discovered to have cytotoxic properties in the 1960s, and by the
end of the 1970s it had earned a place as the key ingredient in the
systemic treatment of germ cell cancers. Among many chemotherapy drugs that are widely used for cancer, cisplatin is one of the
most compelling ones. It was the rst FDA-approved platinum
compound for cancer treatment in 1978 (Kelland, 2007). This has
led to interest in platinum (II)and other metalcontaining compounds as potential anticancer drugs (Frezza et al., 2010).
Cisplatin is clinically proven to combat different types of cancers
including sarcomas, cancers of soft tissue, bones, muscles, and blood
vessels. Although such cancers have recently received better prognosis and therefore have become less life threatening (Desoize and
Madoulet, 2002), signicant challenges remain with regard to their
cure. Also, because of drug resistance and considerable side effects,
combination therapy of cisplatin with other cancer drugs has been
applied as novel therapeutic strategies for many human cancers. In
this research, we aim to provide a comprehensive review of the
physicochemical properties of cisplatin and related platinum-based
drugs, to discuss its uses (either alone or in combination with other
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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 oxaliplation. These platinum compounds are composed of doubly charged platinum ion
surrounded by four ligands; with the amine ligands on the left forming stronger
interactions with the platinum ion, and the chloride ligands or carboxylate
compounds on the right forming leaving groups allowing the platinum ion to form
bonds with DNA bases (Goodsell, 2006).
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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 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 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 et al., 2009; Dhar et al., 2011). The cytotoxic effect
is likely a result of inhibition of replication by cisplatin-DNA
adducts and induction of apoptosis (Siddik, 2003).
3.5. Cisplatin and brain cancer
Glioblastomamultiforme (GBM) is the most common primary
malignant brain tumor, and with rare exception, is invariably fatal
(Stupp et al., 2005). The current standard of care for patients
with GBMs consists of surgery and radiotherapy in combination
with temozolomide, followed by repetitive cycles of temozolomide (Stupp et al., 2009). Although the survival advantage of
this combined treatment regimen was still evident at 5 years, the
increase in overall median survival was only for 2.5 months.
Cisplatin therapy is also used for recurrent childhood brain
tumors(Khan et al., 1982),as well as in other cancers such as
gastric cancer (Koizumi et al., 2008), anal cancer (Ajani et al.,
2008), and leukemia (Previati et al., 2006).
Paclitaxel is a mitotic agent that binds preferentially to microtubules (Parness et al., 1981) and the resulting stabilization
of microtubules inhibits the reorganization of the microtubule
network. Paclitaxel has been demonstrated to be active against
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Table 1
Combination therapy of cisplatin and other cancer drugs.
Combination drug(s)
Cancer type
Reference(s)
Paclitaxel
Bevacizumab
Vinbalstine and bleomycin
Methotrexate and bleomycin
Everolimus
Fluorouracil, doxorubicin and
cyclophosphamide
Metformin
Oxaliplatin, quercetin and thymoquinone
Olaparib
Tetra arsenic oxide
Vindesine
-galactosyl-pyrrolidinyldiazeniumdiolate
Lung adenocarcinoma
Ovarian cancer
PTEN decient lung cancer
Cervical cancer
Non small lung carcinoma
Glial cells of brain Human cervical cancer
Gliosarcoma cell lines
Du et al. (2013)
Colombo et al. (1986)
Dexeus et al. (1991)
Pinto-Leite, et al. (2013)
Dimery et al. (1990)
Lin et al. (2013)
Nessa et al. (2011)
Minami et al. (2013)
Byun et al. (2013)
Le et al. (1994)
Deng et al. (2013)
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study comparing the geometric, electronic, and vibrational properties of cisplatin using different basis sets, including pure ECP and
hybrid ECP with various electron correlation methods up to the
MP4 level, and DFT, was performed (Pavankumar et al., 1999).
Thermodynamics of hydrolysis of cisplatin and bis(ethylenediamine) dichloroplatinum(II) using a combination of molecular
mechanics for obtaining optimized geometries of the reactants
and products, and the extended Huckel method for deriving
charge distributions and electronic energies were studied. This
hydrolysis was studied by several others using various levels of
theory, where a common approach adopted has been to use DFT
to optimize the geometries of the key intermediates and
reevaluate their energies using higher level ab initio methods,
and/or adding solvation corrections based on continuum dielectric models. describes the interaction of transplatin and the
fragments trans-PtCl2(NH3) and Pt(NH3)23 with G:C and A:T
base pairs using DFT, followed by an MP2-based energy analysis
(Nikolov et al., 1994; Mantri and Baik, 2006; Zhang et al., 2001;
Lau and Deubel, 2005).
Cisplatin has been known to bind to guanine with much
greater preference over adenine, which is somewhat surprising
because it could be argued that the inductive effects of the
electron-withdrawing oxo group at the C6 position of guanine
should reduce the electron density at N7 compared to adenine
that has an electron-donating amino group at the C6 position,
thus making the N7 of guanine less nucleophilic compared to
adenine (Mantri and Baik, 2006). The major difference between
guanine and adenine is that N1 of guanine is protonated, while
adenine exposes an N1 lone pair. The presence of the N1 proton
diminishes the delocalization of electron density over the
nitrogen lone pairs of the purine skeleton resulting in greater
localization of electron density on the N3 and N7 atoms of
guanine, compared to adenine where the electron density is
delocalized over the N1, N3, and N7 atoms (Mantri and Baik,
2006). In an attempt to identify yet another subtle electronic
feature that could help in distinguishing between the reactivity
of adenine and guanine, it was discovered that the [Pt] fragment
is a poor -donor; thus -back donation does not appear to play
a major role (Mantri and Baik, 2006).
Cisplatin binds to other cellular components, resulting in either
deactivation of the drug and/or disruption of normal biochemical
pathways. Thus, signicant efforts have focused on understanding
the binding of cisplatin with other entities found in the cells; in
particular S- and N-containing ligands that are expected have the
greatest afnity for platinum based on good hardness- softness
matching. It was reported a thorough DFT study which compared
the PtL bond strengths of a series of tri- ammine platinum(II)
complexes with oxygen-, nitrogen- and sulfur-donor ligands as
models of competing ligands encountered in a biological system
(Deubel, 2002). In another study, the kinetics of the substitution
reaction of various nitrogen- and sulfur ligands with the activated
cisplatin complex was modeled using DFT. This study revealed that
kinetically N-donor ligands were preferred over S-donors, with the
selectivity originating from electrostatic rather than orbital-based
interaction (Deubel, 2004).
Other areas of active study on cisplatin are degree of local
bending/unwinding upon cisplatin binding, the disruption of base
stacking and other local distortions, the thermodynamics of the
various possible adducts, the directional preference in the formation of the bifunctional adducts, the ineffectiveness of transplatin,
the effect of cisplatin binding on the dynamics of DNA, and the
binding and recognition of HMG domain and/or DNA repair
proteins to these adducts (Mantri and Baik, 2006). Computational
models have made signicant contributions to understanding the
nature and reactivity of cisplatin and allowed for delineating many
features of how it binds to DNA.
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7. Conclusions
Cisplatin is one of the most effective anticancer agents widely
used in the treatment of solid tumors. It has been extensively used
for the cure of different types of neoplasms including head and
neck, lung, ovarian, leukemia, breast, brain, kidney and testicular
cancers. In general, cisplatin and other platinum-based compounds are considered as cytotoxic drugs which kill cancer cells
by damaging DNA, inhibiting DNA synthesis and mitosis, and
inducing apoptotic cell death. Several molecular mechanisms of
action including induction of oxidative stress as characterized by
reactive oxygen species production and lipid peroxidation, induction of p53 signaling and cell cycle arrest, down-regulation of
proto-oncogenes and anti-apoptotic proteins, and activation of
both intrinsic and extrinsic pathways of apoptosis. However,
cisplatin chemotherapy is also associated with substantial side
effects that include hepatotoxic, nephrotoxic, cardiotoxic, neurotoxic and/or hematotoxic damage. Also, some patients may relapse
from cisplatin treatment with their cancers being refractory to
cisplatin regimen. Hence, combination therapies of cisplatin with
other drugs are common practice in the treatment of human
cancers. Findings of several studies have suggested that other
compounds combined with cisplatin constitute the best therapeutic approach to overcome drug resistance and reduce the undesirable side effects. Moving forward, combinatorial strategies which
target multiple mechanisms, such as reducing cisplatin uptake and
reducing inammation, may offer the best chance for clinically
meaningful prevention.
Acknowledgments
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.
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