Review Article: Cellular Responses To Cisplatin-Induced DNA Damage

SAGE-Hindawi Access to Research
Journal of Nucleic Acids

Volume 2010, Article ID 201367, 16 pages
doi:10.4061/2010/201367
Review Article
Cellular Responses to Cisplatin-Induced DNA Damage
Alakananda Basu and Soumya Krishnamurthy

Department of Molecular Biology & Immunology, University of North Texas Health Science Center and Institute for Cancer Research,
3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
Correspondence should be addressed to Alakananda Basu, [email protected]
Received 12 May 2010; Accepted 28 June 2010
Academic Editor: Ashis Basu
Copyright © 2010 A. Basu and S. Krishnamurthy. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as
a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced
DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling
pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which
cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin
inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein
kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development
of more effective therapeutic strategies for the treatment of cancer.
1. Introduction The success of cisplatin therapy is compromised due to

dose-limiting toxicity, especially nephrotoxicity as well as
Cisplatin was discovered fortuitously by Dr. Rosenberg in resistance by tumor cells to cisplatin. Cellular resistance to
1965 while he was examining the effect of electromagnetic cisplatin could be either intrinsic or acquired. The clinically
field on bacterial cell growth [1, 2]. Since the active principle acquired resistance can be caused by decreased drug accu-
that inhibited bacterial cell division was identified to be mulation which includes reduced uptake or increased efflux
cisplatin, he anticipated that it would also inhibit the
of cisplatin, increased drug detoxification by cellular thiols,
proliferation of rapidly dividing cancer cells. Cisplatin was
increased DNA repair or tolerance of cisplatin-damaged
indeed demonstrated to possess antitumor activity in a
DNA and the ability of the cancer cells to evade cisplatin-
mouse model [3] and was first used in the clinical trial
almost 30 years ago. Since its approval by the Food and Drug induced cell death. Numerous studies have focused on the
administration in 1978, cisplatin continues to be one of the drug-target interactions, cellular pharmacology, and phar-
most effective anticancer drugs used in the treatment of solid macokinetics of cisplatin. Another active area of research has
tumors. been to develop analogs of cisplatin to minimize toxicity and
Cisplatin has been used as a first-line therapy for circumvent cisplatin resistance.
several cancers, including testicular, ovarian, cervical, head, The antitumor activity of cisplatin is believed to be
and neck and small-cell lung cancers either alone or in due to its interaction with chromosomal DNA [4]. Only
combination with other anticancer agents. It is also used a small fraction of cisplatin, however, actually interacts
as an adjuvant therapy following surgery or radiation. In with DNA and the inhibition of DNA replication cannot
addition to cisplatin, its analogs, such as carboplatin and solely account for its biological activity [5]. In addition,
oxaliplatin, are also currently being used in the clinic. the efficacy of chemotherapeutic drugs depends not only on
However, patients who initially respond to cisplatin therapy their ability to induce DNA damage but also on the cell’s
often develop resistance to the drug during the course of the ability to detect and respond to DNA damage [6]. Following
treatment. DNA damage, cells may either repair the damage and start
2 Journal of Nucleic Acids
progressing through the cell cycle or if they cannot repair the correlates with the sensitivity of ovarian carcinoma cells
damage, cells proceed to die [5]. Cisplatin, like many other to cisplatin [25]. The organic cationic transporters SLC22
chemotherapeutic drugs, can induce apoptosis. Thus, the family of proteins have also been shown to participate in
signaling pathways that regulate apoptosis have significant cisplatin influx [11]. Thus, cisplatin can enter cells by passive
impact on deciding cellular responsiveness to cisplatin. There or facilitated diffusion and by active transport. Depending on
are many excellent reviews on cisplatin and its analogues [7– the cellular context, multiple transporters may be involved in
15]. In this paper, we primarily focused on recent studies cisplatin uptake. Therefore, it is difficult to correlate cisplatin
on cellular responses to cisplatin-induced DNA damage sensitivity/resistance with a particular transporter.
although we briefly discussed steps leading to cisplatin- Many cell lines with acquired resistance to cisplatin often
induced DNA damage. This comprehensive paper should exhibit reduced drug accumulation. Unlike multidrug resis-
not only benefit researchers in the field of cisplatin but also tance (MDR), drug efflux does not appear to be the major
benefit those interested in mechanisms of chemoresistance cause of cisplatin resistance. Kawai et al. first reported that
and targeted therapy. a 200-kDa plasma membrane glycoprotein is overexpressed
in murine thymic lymphoma cells selected for resistance to
cisplatin, which correlated with reduced accumulation of
2. Biotransformation of Cisplatin cisplatin in the cells [26]. The increased expression of this
protein correlated with the degree of cisplatin resistance [26].
Cisplatin or cis-diamminedichloroplatinum(II) is a neutral,
There was, however, no follow-up study to establish the
square-planar, coordination complex of divalent Pt [8]. The
importance of this protein in conferring cisplatin resistance.
cis configuration is required for its antitumor activity [16].
The ATP-dependent glutathione-conjugated efflux pump
It has two labile chloride groups and two relatively inert
and copper transporters ATP7A and ATP7B have been
amine ligands. Cisplatin undergoes hydrolysis in water. The
implicated in cisplatin export [20]. It is generally believed
chloride concentration is an important factor in determining
that reduced cisplatin accumulation in cisplatin resistant
the hydrolysis or aquation of cisplatin. The high chloride
cells is due to decrease in uptake of cisplatin rather than an
concentration (∼103 mM) of blood plasma prevents the
increase in drug efflux [7, 27].
hydrolysis of cisplatin. Upon entering the cell, the chloride
concentration drops down to 4 mM which facilitates the
aquation process [17]. The aquated form of cisplatin is a 4. Formation and Repair of
potent electrophile and reacts with a variety of nucleophiles, Cisplatin DNA Adduct
including nucleic acids and sulfhydryl groups of proteins.
DNA is thought to be the primary biological target of
cisplatin [17, 28, 29]. The platinum atom of cisplatin forms
3. Accumulation of Cisplatin Inside Cells covalent bonds with the N7 position of purine bases to form
1,2- or 1,3-intrastrand crosslinks and a lower percentage
Cisplatin and its analogues were initially thought to enter
of interstrand crosslinks. Cisplatin resembles bifunctional
cells by passive diffusion because cisplatin uptake was linear,
alkylating agents. The intrastrand crosslink between two
nonsaturable and could not be competed with platinum
adjacent G residues is believed to be the critical lesion
analogs [4–6, 17]. Although decreased accumulation of
responsible for cisplatin cytotoxicity. Formation of cisplatin-
cisplatin is often associated with acquired resistance to
DNA adducts interferes with DNA replication and tran-
cisplatin, few or no changes were observed in the plasma
scription. The interstrand and intrastrand crosslinks disrupt
membrane function in the cisplatin-resistant cell lines as
the structure of the DNA. This alteration in the structure
compared to the parental cells [18–20]. In 1981, it was
is recognized by the cellular proteins to repair cisplatin-
first proposed that cisplatin could be transported actively
induced DNA damage. Increased repair of cisplatin-induced
via the carrier-mediated transport [21]. Several transporters,
DNA damage has been associated with cisplatin resistance.
including the Na+ , K+ -ATPase [22] and members of solute
carrier (SLC) transporters [11] have been implicated in
facilitating the entry of cisplatin into the cells. The plasma 4.1. Cisplatin and Nucleotide Excision Repair Pathway. Since
membrane copper transporter-1 (CTR1), a member of the the intrastrand cross-link is the major lesion caused by
SLC family, gained particular attention since a defect in cisplatin-induced DNA damage, it is primarily repaired via
Ctr1 gene decreased cisplatin accumulation in yeast [23, 24]. the nucleotide excision repair (NER) system. Xeroderma
In addition, cisplatin and carboplatin accumulation was Pigmentosum (XP) is a disorder caused by deficiency of
attenuated in mouse embryonic fibroblasts from ctr1−/− genes involved in NER. Cells derived from XP patients
animals compared to wild-type animals [18]. Interestingly, are exquisitely sensitive to cisplatin [30]. In addition, the
both copper and cisplatin were shown to cause rapid favorable response of testicular cancer to cisplatin was
downregulation of CTR1 in ovarian cancer cells by the associated with low levels of XP complementation group
proteasome-mediated pathway [19]. While CTR1 appears to A (XPA) and excision repair cross-complementation group
transport cisplatin and its analogs, there is little decrease I (ERCCI), which participate in NER [31, 32]. A number
in CTR1 when cells acquire resistance to cisplatin. A recent of studies correlated the overexpression of ERCC1 or XPA
study demonstrated that copper transporter-2 or CTR2 proteins with cisplatin resistance [31–34]. The existence of
limits accumulation of cisplatin and the level of CTR2 ERCC1 exon VIII alternative splicing was observed in ovarian
Journal of Nucleic Acids 3
cancer cells [35]. Although this splicing did not affect the DNA lesions formed by cisplatin [48–50], and mutations in
level of ERCC1, it decreased its excision repair function. MSH1 or MLH1 genes of the MMR system were observed
In addition, epigenetic changes, such as hypermethylation in cisplatin-resistant cells [51–53]. Recently, the proapop-
of ERCC1, which inversely correlated with ERCC1 mRNA totic function of cisplatin was shown to be mediated in
levels, have been suggested as a mechanism for enhanced an MSH2/MSH6-dependent manner [54]. MLH1-proficient
cisplatin sensitivity [36]. A recent study demonstrated that cells were more sensitive to cisplatin compared to MLH1-
XPA binding domain of ERCC1 was required for the repair deficient cells. Cell death by cisplatin was associated with
of cisplatin-damaged DNA [37]. A double knockdown of significant proteolysis of MLH1, caused by destabilization of
XPF/ERCC1 complex was shown to be very effective in X-linked inhibitor of apoptosis protein (XIAP), resulting in
enhancing cisplatin sensitivity in non-small cell lung cancer caspase activation [55]. The repair function of MMR pro-
cells [38]. An antisense DNA against XPA sensitized lung teins has been reported to be uncoupled from their function
adenocarcinoma cells to cisplatin [34]. Recently, it has been in mediating cisplatin-induced cell death [56–58]. Since the
reported that treatment of rat spiral ganglion neurons with primary mechanism of cisplatin involves DNA damage and
cisplatin induced the mRNA levels of XPA and XPC along p53 is also involved in DNA damage signaling, there are many
with nuclear translocation of these enzymes, thus decreasing studies that correlate cisplatin and DNA damage and repair
the rate limiting step in the NER pathway [39]. This can with p53 activity [59–62]. It has been reported that cisplatin
provide a plausible mechanism by which cisplatin induces enhances the interaction between mismatch repair protein
NER. Kang et al. made an interesting observation that XPA MLH1/postmeiotic segregation increased 2 (PMS2) and
was regulated in a circadian fashion in the mouse liver, but p73 triggering apoptosis in mismatch repair-proficient cells
not in the testis [40]. Removal of cisplatin-DNA adducts [60].
also followed a circadian pattern in the extracts derived from
the liver. The authors proposed that chronochemotherapy
could be more effective in the treatment of cancers in which 5. Interaction of Cisplatin with Cellular Thiols
XPA removes cisplatin-DNA adducts in a circadian fashion.
Although the major target of cisplatin is the nuclear DNA,
Thus, the cisplatin-induced DNA repair employing the NER
it exhibits a high affinity towards sulfur donors such as
process is multilayered including epigenetic, transcriptional,
cysteines and methionines forming stable Pt-S bonds. This
and posttranslational regulation.
competes with the affinity towards the nitrogen atom in
NER is also linked to the cellular signaling pathways.
the DNA thus contributing towards resistance against the
It has been reported that the NER process may prevent
cytotoxic action of cisplatin [63]. The abundant intracellular
cisplatin-induced apoptosis by activating the ataxia telang-
thiols involved in the drug resistance are glutathione and
iectasia mutated (ATM) pathway which is recruited to the
metallothionein.
damaged DNA through XPC [41]. Lack of functional p53
has been associated with persistence of cisplatin-induced
intrastrand cross-links, suggesting the importance of p53 in 5.1. Interaction of Cisplatin with Glutathione. When cancer
regulating NER of cisplatin-damaged DNA [42]. Functional cells are exposed to cisplatin, the platinum atom in cisplatin
NER was also required for cisplatin-induced transcription of is chelated by glutathione (GSH) and the glutathione-Pt
Bcl-xL via nuclear factor-kappa B (NF-κB) [43]. complex is effluxed from the cell in an ATP-dependent
In addition to NER, cisplatin can also induce tran- manner by the glutathione transporter family, termed the
scription-coupled repair (TCR). The intrastrand crosslink GS-X pumps [64]. It was initially noted that cells that
stalls RNA polymerase II to trigger TCR [44]. It has are resistant to cisplatin have elevated levels of glutathione
been reported that p53 protects against cisplatin-induced [65]. However, recent studies with cisplatin-resistant cancer
apoptosis in a TCR-dependent manner [30]. In addition, the cell lines seem to suggest otherwise [66, 67]. Based on
homology-directed DNA repair (HR) that allows error-free NMR studies, Kasherman et al. reported that the higher
repair of the double-strand breaks caused by the excision of levels of GSH do not correlate with decreased sensitivity
cisplatin-DNA adducts has been implicated in the repair of to cisplatin [68]. In agreement with this study, Chen et
cisplatin-induced DNA damage [45]. It has been reported al. suggested that increased levels of GSH might sensitize
that mouse mammary tumors containing irreparable null cells to cisplatin by upregulation of the copper transporter
alleles of Brca1 gene, which is involved in DNA double strand hCtr1 [69]. Therefore, whether overexpression of glutathione
break repair, do not become resistant to cisplatin. Bypass contributes to or combats cisplatin resistance is still under
of cisplatin-DNA adduct has also been associated with debate.
cisplatin resistance. DNA polymerase-eta could replicate Apart from GSH, the glutathione S-transferase P1-1
across intrastrand cross-link between cisplatin and two (GSTP1-1) enzyme has also been associated with resistance
adjacent G residues [46]. to cisplatin-based chemotherapy [70, 71]. Pasello et al.
demonstrated that increased levels of GSTP1 were asso-
4.2. Cisplatin and Mismatch Repair Pathway. Mismatch ciated with cisplatin resistance in osteosarcoma cell lines
repair (MMR) system recognizes cisplatin-induced DNA and a higher relapse rate and poor prognosis in high-
damage, but instead of increasing cell viability, MMR system grade osteosarcoma patients [72]. In contrast, a recent
was shown to be important for cisplatin-mediated cytotoxi- study by Peklak-Scott et al. suggested that a high level
city [47]. DNA mismatch repair protein, MutSα recognized of cisplatin resistance may not be due to conjugation of
cisplatin to glutathione by GSTP1 [73]. Other enzymes in which is primarily degraded via the ubiquitin proteasome-
the glutathione transferase family, such as the GSTμ or mediated pathway [30, 88]. The E3 ubiquitin ligase Mdm2 is
the GSTO1-1, have also been implicated in contributing a transcriptional target of p53 and regulates p53 expression
towards cisplatin resistance [74, 75]. Thus, although a via a negative feedback loop [30]. DNA damage results
great deal of work has been focused on the correlation of in the activation of ATM and/or ATM- and Rad3-related
glutathione and its conjugating enzymes towards cisplatin (ATR), resulting in phosphorylation and stabilization of
resistance, further studies are needed to explore this in p53 [88]. p53 can transactivate genes involved in cell cycle
detail. progression (e.g., p21), DNA repair (e.g., growth arrest and
DNA damage-inducible 45, GADD45), and apoptosis (e.g.,
5.2. Interaction of Cisplatin with Metallothionein. Metalloth- Bax) [89].
ioneins (MT) are cysteine-rich proteins, which consist of 61- Fujiwara et al. first demonstrated that adenoviral-
68 amino acids of which 20 are cysteins. The four isoforms of mediated delivery of p53 into small-cell lung cancer cells
MTs (MT1-MT4) are ubiquitously expressed in humans and induced massive apoptosis both in monolayer cultures and
are inducible by a variety of drugs, including cisplatin [76]. in tumor xenografts upon treatment with cisplatin [90].
They are involved in zinc and copper homeostasis, heavy Introduction of wild-type p53 by adenovirus vector also
metal detoxification, and protection from apoptosis. Initial sensitized ovarian cancer cells to cisplatin [91–93]. Several
reports observed an increased expression of metallothionein proteins, including cyclin-dependent kinase inhibitor p21,
correlating with cisplatin resistance in ovarian carcinoma ATR, and checkpoint kinase (CHK2) have been implicated
cell lines [77]. We have also seen that a wide variety of in p53-mediated apoptosis [94–97]. In addition, tumor cells
human cancer cell lines with acquired resistance to cisplatin lacking functional p53 were more resistant to cisplatin than
overexpressed metallothionein and ectopic expression of cells that contained functional p53 and the resistant cell lines
metallothionein conferred cisplatin resistance [78]. Recent were sensitized to cisplatin upon reconstitution with wild-
reports also suggest that the increased expression of metal- type p53 [98, 99]. p53 itself has been shown to bind cisplatin-
lothionein correlates with cellular resistance against cisplatin modified DNA [100]. In addition, cisplatin was shown to
[79–81]. induce nitrosylation of p53 preventing its mitochondrial
translocation [101].
The ubiquitously occurring metallothionein isoforms, p53 can regulate cisplatin-induced cell death by several
MT-1 and MT-2, have been shown to react faster with mechanisms. Degradation of FLIP (FLICE-like inhibitory
cisplatin [82], compared to glutathione [83, 84]. The basal protein) has been reported to be necessary for p53-induced
levels of MT-1 and MT-2 are often significantly increased in apoptosis in response to cisplatin [102, 103]. p53 also pro-
cancer cells [78, 85], resulting in even stronger scavenging motes cisplatin-induced apoptosis by directly binding and
of divalent platinum, and contributing to acquired resistance counteracting the antiapoptotic function of Bcl-xL [104].
against cisplatin [78, 86, 87]. MT-3 isoform was initially Although the phosphatase and tensin homolog (PTEN) is
thought to be unresponsive to the platinum drugs [81]. believed to inhibit phosphoinositide 3-kinase (PI3K)/Akt,
Recent reports, however, suggest that MT-3 is overexpressed overexpression of PTEN was shown to involve p53-mediated
in hypoxic conditions, and the reaction between MT-3 apoptotic cascade in cisplatin-resistant ovarian cancer cells
and Pt(II) is kinetically preferred [81]. The authors further independent of PI3K/Akt pathway [105]. The nutrient-
proposed that the Zn(II) released from this reaction can sensor AMP-kinase (AMPK) was shown to be activated by
result in the upregulation of the MT-1 and MT-2 isoforms. cisplatin in AGS and HCT-116 cancer cells and inhibition
Thus, metallothionein isoforms play an important role in of AMPK enhanced cisplatin-induced apoptosis by causing
contributing towards cisplatin resistance. hyperinduction of p53 [106].
One of the major side effects of cisplatin therapy is
6. Cisplatin and DNA Damage Signaling nephrotoxicity and the involvement of p53 in cisplatin-
induced nephrotoxicity has been investigated. p53 induced
Various stress signals generate DNA lesions that may lead proapoptotic Bcl-2 family member PUMAα in renal tubular
to mutations and genomic instability. Following DNA dam- cells upon treatment with cisplatin, and dominant-negative
age, cell cycle checkpoints are activated to delay cell-cycle p53 suppressed the expression of PUMAα. This study was
progression to provide time for DNA repair or eliminate extended in C57 mice. Acute renal failure upon cisplatin
genetically unstable cells by inducing cell death. It is treatment was abrogated in p53-deficient C57 mice and this
now recognized that inhibition of DNA replication is not was associated with little or no induction of PUMAα [107].
sufficient to explain cisplatin cytotoxicity. How cells respond CHK2 has also been implicated in apoptosis of renal cells
to cisplatin-induced DNA damage plays a major role in the and tissues as a result of cisplatin-induced p53 activation
ultimate decision whether a cell should live or die following [94]. A study by Yang et al. revealed that caspase-6 and -7
cisplatin treatment. are transcriptional targets of p53 [108]. Thus, induction of
p53 by cisplatin resulted in the activation of these caspases
6.1. p53 and Cisplatin-Induced DNA Damage Response. The contributing to nephrotoxicity [108]. Inhibition of p53
tumor suppressor protein p53 is considered as the “guardian by pharmacological inhibitor or knockout of p53 in mice
of genome”. It plays a critical role in eliciting cellular suppressed caspase-6 and -7 transactivation and protected
responses to DNA damage. p53 is a short-lived protein against nephrotoxicity. Recently, microRNAs have also been
shown to play a major role in cisplatin nephrotoxicity. miR- phosphorylate Yap1, increasing its stability and affinity for
34a is induced by cisplatin via p53 and plays a cytoprotective p73 [127]. Phosphorylation of Yap1 can dictate whether p73
role in the survival of proximal tubular cells [109]. will transactivate proapoptotic or growth arrest genes [127].
Although a plethora of literature exists on the role of A recent study suggests that c-Abl can regulate the function
p53 in contributing towards cisplatin cytotoxicity, p53 has of p63. Phosphorylation of p63 at Tyr residue by c-Abl
also been associated with cisplatin resistance. MCF-7 breast stabilizes it causing an increase in its proapoptotic function
cancer cells containing wild-type p53 are highly resistant [128].
to cisplatin but disruption of p53 by the introduction of Cisplatin can trigger cleavage of c-Abl which is a substrate
human papilloma virus (HPV) in MCF-7 cells sensitized for caspase and proteolytic cleavage of c-Abl was shown to be
these cells to cisplatin [110]. Ovarian cancer cells selected for important for cisplatin-induced apoptosis [129]. Activation
cisplatin resistance exhibited higher levels of p53 compared of p38 MAPK is critical for regulating cisplatin activity.
to cisplatin-sensitive counterpart [111]. Although p53 level Galan-Moya et al. [130] recently reported that c-Abl activates
is low in HeLa cells due to degradation of p53 by HPV, it was p38 MAPK independent of its tyrosine-kinase activity but
elevated in cisplatin-resistant HeLa cells [112]. Studies have by stabilizing MKK6, the upstream kinase of p38 MAPK.
also shown that mutations in p53 contributed to cisplatin This study provides an explanation why the c-Abl inhibitor
resistance in different cancer models [113–116]. imatinib fails to inhibit p38 MAPK [130]. Thus, c-Abl is
Although p53 plays an important role in cisplatin- an important mediator of cisplatin-induced DNA damage
induced DNA damage response, p53-negative cells also response and acts in cooperation with the siblings of p53 and
respond to cisplatin-induced DNA damage, suggesting alter- MAPK pathways to trigger cisplatin-induced apoptosis.
nate pathways of sensing cisplatin-induced DNA damage.
6.2. c-Abl and Cisplatin-Induced DNA Damage Response.

7. Regulation of Cisplatin-Induced Cell Death
The tyrosine kinase c-Abl plays an important role in stress by Protein Kinases
response to DNA damaging agents. It belongs to the non-
Cisplatin primarily induces cell death by apoptosis and a
receptor tyrosine kinases and contains nuclear localization
defect in apoptotic signaling could also confer cisplatin
motifs and nuclear export signals. Thus, it can shuttle
resistance. There are two major pathways of cell death [131,
between the nucleus and cytoplasm. Nuclear import of c-
132]. The extrinsic pathway is initiated when ligands bind
Abl was shown to be necessary for DNA damage-induced
to the tumor necrosis factor-α (TNFα) receptor superfamily
apoptosis [117]. It is activated in response to cisplatin
followed by oligomerization and recruitment of procaspase-
causing activation of c-Jun-N-terminal kinase (JNK)/stress-
8 via adaptor molecules to form the death-inducing signaling
activated protein kinase (SAPK) [118]. c-Abl-deficient cells
complex (DISC). The intrinsic pathway is initiated by
fail to activate JNK. Nuclear c-Abl can associate with and
cellular stress, such as DNA damage, resulting in release
phosphorylate MEK kinase 1 (MEKK1) in response to DNA
of cytochrome-c from the mitochondria causing activation
damage resulting in the activation of JNK/SAPK [119].
of procaspase-9 through the interaction with apoptosis
Nehmé et al. [120] demonstrated that activation of c-Abl
promoting activating factor-1 (APAF-1) and formation of an
and JNK is contingent upon the recognition of cisplatin-
active apoptosome complex. Bcl-2 family proteins regulate
induced DNA damage by the MMR system since c-Abl
DNA damage-induced apoptosis by regulating the release of
response is absent in MMR-deficient cells. They further
mitochondrial cytochrome c in response to DNA damage.
demonstrated that the activation by these pathways is specific
Cisplatin-induced genotoxic stress activates multiple signal
to cisplatin and not to the cisplatin analogue oxaliplatin,
transduction pathways, which can contribute to apoptosis or
thus highlighting the importance of the MMR system to
chemoresistance.
specifically recognize cisplatin-DNA adducts [120, 121].
Interestingly, MMR/c-Abl cooperates with p73, a mem-
ber of the p53 family, to trigger apoptosis [122]. Cisplatin 7.1. Cisplatin and Protein Kinase C. Protein kinase C (PKC) is
caused induction of p73 in several cancer cell lines and in a family of closely related phospholipid-dependent enzymes
mouse embryonic fibroblasts (MEF), which were proficient that play critical roles in signal transduction and cell regu-
in mismatch DNA-repair pathway but not in MEF deficient lation [133–136]. Based on the structure and biochemical
in c-Abl or MMR [122]. Activation of c-Abl in response properties they are grouped as conventional (α, βI, βII,
to cisplatin led to phosphorylation and stabilization of and γ), novel (δ, ε, η, and θ) and atypical (ζ and ι) PKCs.
p73 [123, 124]. Phosphorylation of p73 can also increase Tumor-promoting phorbol esters are potent activators of
its proapoptotic function by dissociating itself from p63, PKCs but persistent treatment with phorbol esters can induce
another member of the p53 family. p63 can bind to and downregulation or degradation of phorbol ester-sensitive
counteract the proapoptotic function of p73 [125]. In conventional and novel PKCs.
addition, c-Jun was shown to enhance p73 stability and We inadvertently found that the PKC signal transduction
transactivation activity by preventing its degradation via the pathway can regulate cisplatin sensitivity. In the meantime,
proteasomal pathway [126]. Binding of the transcription Hofmann et al. reported that inhibition of PKC by quercetin
coactivator Yap1 also prevents proteasomal degradation of or downregulation of PKC by the phorbol ester, 12-O-
p73 and results in the recruitment of p300 to trigger tetradecanoylphorbol-13-acetate (TPA) could enhance the
transcription of proapoptotic genes. c-Abl can directly antiproliferative activity of cisplatin [137]. In contrast,
Isonishi et al. [138] and we [139] simultaneously reported can also regulate cisplatin-induced activation of caspase-3
that activation of PKC by phorbol esters could enhance [154]. These studies were based on the effect of rottlerin,
sensitivity of human ovarian cancer 2008 and human cervical a pharmacological inhibitor of PKCδ on cisplatin-induced
cancer HeLa cells to cisplatin. There were contrasting reports apoptosis [155]. Although rottlerin caused downregulation
whether activation or downregulation of PKC was necessary of caspase-2 and inhibition of cisplatin-induced apoptosis,
for cisplatin sensitization [138, 140]. Although TPA is a the effect of rottlerin on caspase-2 downregulation was not
useful tool as a pharmacological agent to study PKC function, due to inhibition of PKCδ [156]. The effect of PKCδ on
it is a tumor promoter and therefore cannot be used in cisplatin-induced apoptosis depends on the cellular context.
the clinic. We first showed that bryostatin 1, a partial PKC In gastric cancer MKN28 cells, PKCδ was shown to enhance
agonist which lacks tumor promoting activity, also sensitized cisplatin-induced caspase activation and cell death via p53
HeLa cells to cisplatin [141]. Based on the preclinical studies, [157]. Overexpression of PKCδ or caspase cleavage-resistant
Phase II trial using combination of bryostatin 1 and cisplatin mutant of PKCδ had little effect on cisplatin-induced cell
was initiated in advanced recurrent cervical carcinoma but death in human small-cell lung cancer H69 cells which have
was not very effective [142]. Combination of bryostatin 1 mutated p53 [158]. On the other hand, knockdown of PKCδ
and cisplatin had minimal toxicity in patients with refractory enhanced cisplatin-induced cell death in thyroid cancer by
nonhematological malignancies although only four patients decreasing fos expression [159].
achieved an objective response [143]. This may be because We have shown that overexpression of PKCε contributes
bryostatin 1 is a partial agonist and its regulation is complex. to cisplatin resistance by inhibiting cisplatin-induced apop-
One of the caveats with these earlier studies to define tosis [160]. Integrative genomic approach has identified
the role of PKC in regulating cisplatin sensitivity was that PKCι as a potential oncogene for ovarian carcinoma [161].
PKC activation and downregulation was monitored based It has also been associated with chemoresistance of glioblas-
on PKC activity assay which does not discriminate among toma multiforme, an aggressive form of brain cancer [162].
PKC isozymes. We now know that PKC isozymes may have The mechanism of PKCι-mediated chemoresistance involved
distinct and even opposite effects on cisplatin-induced cell inhibition of p38 MAPK [162]. A recent study suggests
death [144]. Another shortcoming with these studies was the that atypical PKCζ can counteract the ability of cisplatin
use of pharmacological agents that lack absolute specificity to decrease matrix metalloproteinase-2 secretion [163].
to PKC. Thus, the effects of PKC on cellular sensitivity/resistance to
An increase in novel PKCδ or -ε and a decrease in cisplatin depend on the pattern of the PKC isozymes as well
conventional PKCs have been associated with acquired as on the cellular context.
resistance to cisplatin [145]. However, inhibition of PKCα
by Gö 6976 and depletion of PKCα by siRNA enhanced 7.2. Cisplatin and MAPK. Mitogen-activated protein kinases
sensitivity of both parental and cisplatin-resistant HeLa cells (MAPK) are a family of structurally-related serine/threonine
to cisplatin [146]. Antisense oligonucleotides against PKCα protein kinases that coordinate various extracellular signals
enhanced the antitumor activity of cisplatin against human to regulate cell growth and survival [164–166]. There are
breast cancer MCF-7, prostate cancer PC3, and human three major subfamilies of MAPK: extracellular signal-
small cell carcinoma H69 cells transplanted in nude mice regulated kinase (ERK)-1 and -2, stress-activated protein
[147]. Additionally, antisense oligonucleotide against PKCα kinase (SAPK)/c-Jun N-terminal kinase (JNK) and p38
in combination with cisplatin was effective in patients with MAPK. All three MAPKs have been implicated in regulating
non-small cell lung cancer [148]. Furthermore, although cisplatin-induced cell death.
PKCα was downregulated in cisplatin-resistant A2780 cells, ERK is activated in response to growth factors and
introduction of PKCα in these cells attenuated cisplatin mitogens. Cisplatin has been shown to cause activation
sensitivity [149]. A recent study demonstrated that inhibition of ERK in several cell types although there are contro-
of PKCβ by enzastaurin enhanced cisplatin sensitivity via versies whether activation of ERK prevents or contributes
dephosphorylation of p90 ribosomal S6 kinase and Bad to cisplatin-induced cell death [167–173]. ERK has been
[150]. These results suggest that conventional PKCα and shown to function as a prosurvival protein in ovarian
-β function as antiapoptotic proteins. It is not clear why a cancer [102, 174], melanoma [175], cervical cancer SiHA
decrease rather than an increase in cPKCs was associated with [176], human myeloid leukemic [177], and gastric cancer
cisplatin resistance. [178] cells. High basal nuclear phospho-ERK2 was asso-
The observation that PKCδ is a substrate for caspase- ciated with cisplatin resistance of ovarian cancer OVCAR-
3 [151] established the importance of this PKC isozyme in 3 cells [179]. Furthermore, nanoparticle-mediated delivery
apoptotic signaling. It has been reported that treatment of of MEK inhibitor PD98059 enhanced antitumor activity
cisplatin-resistant human squamous cell carcinoma SCC- of cisplatin in melanoma-bearing mice [180]. Cisplatin-
25 (SCC25/CP) cells to cisplatin failed to induce caspase-3 induced ERK activation precedes p53-mediated DNA dam-
activation and cleavage of PKCδ due to an increase in anti- age response since ERK directly phosphorylates p53 causing
apoptotic Bcl-xL [152]. Interestingly, the effect of bryostatin upregulation of p21, GADD45, and Mdm2 [181]. Thus,
1 on caspase activation and PKCδ downregulation followed activation of ERK may cause cell cycle arrest allowing
similar biphasic concentration response in both parental and time for the repair of cisplatin-induced DNA damage via
cisplatin-resistant HeLa cells [146, 153]. We have shown p53. ERK also induced phosphorylation of BAD at Ser112
that PKCδ not only acts downstream of caspase-3 but it site in response to cisplatin in ovarian cancer cells, and
inhibition of ERK by PD98059 or mutation of Ser112 involved in MMR system that recognizes the cisplatin-DNA
to Ala sensitized cells to cisplatin [174]. In SiHA cells, adducts and induce cell death [121]. In addition to its role
phosphorylation and activation of NF-κB were associated in regulating anticancer activity of cisplatin, JNK pathway
with the prosurvival function of ERK [176]. Glutathione- has also been implicated in the nephrotoxicity induced by
mediated cisplatin transport and GSTP1 expression also cisplatin. Inhibition of the JNK pathway was cytoprotective
contributed to the antiapoptotic function of ERK in human restricting renal cell death and inflammation [201]. Recently,
myeloid leukemic cells [177] and gastric cancer cells [178], the JNK pathway was also shown to mediate cisplatin-
respectively. Recently, it has been reported that ovarian induced nephrotoxicity driven by the Toll-like receptor,
cancer cells grown in three-dimensional cultures acquired TLR4 [202].
resistance to anoikis and apoptosis when exposed to clinically
relevant concentrations of cisplatin [167]. This resistance 7.4. Cisplatin and p38 MAPK. The p38 MAPK family is acti-
was mediated by the ERK1/2 signaling and the PI3K/Akt vated by environmental stress and inflammatory cytokines
pathway. ERK signaling was also shown to be activated and is an important mediator of cisplatin-induced apoptosis.
when stimulated by inducers such as the cigarette smoke- The activation of this pathway by cisplatin has been seen
carcinogen NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1- in different experimental model systems, resulting in a
butanone], causing cisplatin resistance [182]. cisplatin-sensitive phenotype [203]. Inhibition of p38 MAPK
ERK activation was also shown to be required for rendered cells resistant to cisplatin and restimulation of the
cisplatin-induced apoptosis in cervical cancer HeLa cells p38 MAPK along with JNK sensitized cisplatin resistant
[168, 169, 173], osteosarcoma and neuroblastoma cells [183], ovarian cancer 2008/C13∗ cells by increasing the expression
testicular germ cell tumors [184], glioma cells [185], renal of FasL [204]. Akt2 has been shown to negatively regulate
epithelial cells [186], nasopharyngeal carcinoma cells [187], the p38 MAPK pathway by binding to and phosphorylating
and human small cell lung cancer cells [188]. Decrease one of the p38 family members ASK1, resulting in the
in ERK level/phosphorylation was associated with cisplatin inhibition of this pathway and rendering the cells resistant
resistance in HeLa cells [168, 173]. Cisplatin-induced activa- to cisplatin [205]. The p38 MAPK pathway was shown
tion of p53 was associated with proapoptotic effect of ERK1/2 to be activated in response to agents such as curcumin
in B104 cells [189], whereas cisplatin-induced acute renal which induced apoptosis in cisplatin-resistant ovarian cancer
failure (ARF) in mice was attributed to increase in TNFα gene cells [206]. Thus, the activation of p38 MAPK regardless
expression by ERK and activation of caspase-3 [190]. We of the upstream signaling pathway seems to be important
have found that knockdown of PKCδ attenuates cisplatin- in mediating cisplatin-induced cytotoxicity. Winograd-Katz
induced ERK activation and apoptosis [173], suggesting that and Levitzki identified EGFR as a substrate for p38 MAPK
PKCδ acts upstream of ERK1/2 to trigger cisplatin-induced and cisplatin-induced receptor internalization was triggered
apoptosis. by p38-mediated phosphorylation of the receptor [207]. p38
MAPK has been shown to mediate its effect via p18(Hamlet),
7.3. Cisplatin and JNK. c-Jun N-terminal kinase or stress- a p38 MAPK-regulated protein, which interacts with p53 and
activated protein kinase is activated by various stress stimuli, stimulates the transcription of proapoptotic genes PUMA
including DNA damage. The involvement of the JNK and NOXA to induce apoptosis [208]. Like JNK, p38 MAPK
pathway in cisplatin-induced apoptosis began when it was has also been implicated in contributing to nephrotoxic-
seen that cells defective in JNK pathway were resistant to ity possibly via TNFα [209, 210]. Thus, the p38 MAPK
cisplatin [191]. Although both cis and transplatin activated pathway plays a critical role in regulating cisplatin-induced
the JNK pathway, the kinetics of JNK activation was distinct apoptosis.
[192]. Slow and persistent activation of JNK by cisplatin
as opposed to rapid and transient activation of JNK by 7.5. Cisplatin and Akt. Akt belongs to a family of ser-
transplatin may explain the ability of cisplatin to induce cell ine/threonine kinases which act downstream of phospho-
death. The observation that p73, a proapoptotic member inositide 3-kinase (PI3K) and plays a critical role in cell
of the p53 family, forms a complex with JNK leading to survival [211]. Several studies have established the involve-
cisplatin-induced apoptosis, provides a mechanistic basis ment of Akt in contributing to the acquired resistance to
of how JNK activation leads to cisplatin-induced apoptosis cisplatin in several cancers, including ovarian [174, 212],
[193]. A mutation in the binding sites of JNK reduced p73- uterine [213], small-cell lung cancer [214], nonsmall-cell
mediated apoptosis. In addition, JNK has been involved lung cancer [215] and hepatoblastoma [216]. Hayakawa et
in cisplatin-induced cytotoxicity mediated by the latent al. first demonstrated that cisplatin-induced DNA damage
membrane protein-1 (LMP-1) of the Epstein-Barr virus caused phosphorylation of BAD at Ser136 via Akt and
[190, 194] and phospholipase A2-activating protein (PLAA) inhibition of Akt sensitized ovarian cancer cells to cisplatin
[195]. Furthermore, inhibition of TWIST [196], Snail [197], [174]. Asselin et al. provided evidence that the X-linked
cytokeratin-8 [198], and the RNA-dependent protein kinase inhibitor of apoptosis (XIAP) inhibits cisplatin-mediated cell
(PKR) [199] has been reported to induce JNK activation death in cisplatin-sensitive A2780 ovarian cancer cells via
leading to cisplatin-mediated cytotoxicity. Studies have also phosphorylation and activation of Akt [217]. On the other
implicated activation of JNK pathway following recognition hand, Dan et al. demonstrated that XIAP is a substrate for
of cisplatin-induced DNA damage by the MMR [121, 200]. Akt and phosphorylation of XIAP by Akt prevents its ubiqui-
JNK and c-Abl were proposed to be signal transducers tination and degradation in response to cisplatin, suggesting
Cl Cl
[2] Pt Pt
B
ATP7A/7
NH3 NH3
[1]
1
CTR
Cl Cl
Mitochondria
-X
Pt
GS
NH3 NH3
[3]
Bc Metallothionein
l-X Pt Glutathione
PU Pt
L
M
Aα
p53
[7] m
PTEN iR miR-34a
-2
1 4 DNA repair
ERK (NER)
FLIP
Caspase-9 p53 ATM/ATR
[5]
Akt NH3 NH3
Caspase-6, -7
p21
Caspase-3 Pt
[6] DNA
c-Abl
[4]
p38 MAPK p73
PKC
JNK DNA synthesis
Cell cycle arrest
Apoptosis
ERK
Mismatch repair
Figure 1: Cellular responses to cisplatin-induced DNA damage. [1] Entry of cisplatin into cells by passive diffusion (indicated by dotted
arrows), carrier-mediated transport, employing copper transporter-1 (CTR1). [2] Efflux of cisplatin from the cells by the ATP-dependent
transporters, ATP7A and ATP7B. [3] Cisplatin binds to cellular thiols, such as glutathione and metallothionein. The glutathione-cisplatin
conjugates are further transported from the cells by the ATP-dependent, GS-X pumps. [4] Once cisplatin interacts with DNA, it stalls cell
proliferation by inhibiting DNA synthesis, followed by activation of DNA damage response. [5] Cisplatin-DNA adducts is primarily repaired
via the nucleotide excision repair (NER) system and also induces cell-cycle arrest. The DNA damage response is transduced mainly via p53
and c-Abl. Cisplatin-induced DNA damage activates p53, leading to the induction of p21, GADD45, proapoptotic PUMAα, caspase-6, -7,
and microRNAs such as miR-34a. p53 also promotes cisplatin-induced apoptosis by binding and inhibiting the antiapoptotic Bcl-xL and also
by degradation of FLIP. Cisplatin-DNA adducts activates the mismatch repair system which further activates c-Abl, leading to the activation
of JNK and p38 MAPK and stabilization of p73 resulting in apoptosis. [6] Kinases such as PKC, ERK, and Akt are also involved in the
regulation of cisplatin-induced cell death. [7] miR-214 promotes cisplatin resistance by downregulating PTEN and activating Akt.
that XIAP promotes cell survival acting downstream of containing wild-type p53 but not in A2780/CP cells con-
Akt [218]. In small-cell lung cancer cells, the antiapoptotic taining mutant p53 [105]. It has been suggested that Akt
protein survivin appears to mediate the effect of Akt in promotes chemoresistance by decreasing p53 phosphoryla-
protecting against cisplatin-induced cell death [214]. tion and PUMA upregulation [219]. Heat shock protein,
PI3K/Akt inhibitor not only sensitized ovarian cancer HSP27 which is often overexpressed in cisplatin-resistant
cells to cisplatin in vitro but also enhanced the antitu- cells enhanced cisplatin-induced Akt phosphorylation, sug-
mor activity of cisplatin in nude mice implanted with gesting that HSP27 may contribute to chemoresistance via
Caov-3 human ovarian cancer xenograft [212]. Cisplatin the Akt pathway [220]. Among the Akt isoforms, Akt2
increased p53 and decreased XIAP in cisplatin-sensitive has been associated with chemoresistance of ovarian and
ovarian cancer 2008 cells but not in cisplatin-resistant uterine cancers [205, 213, 221]. However, acquisition of
variant 2008/C13∗ cells unless Akt was inhibited. The status resistance by human lung cancer cells was associated with
of p53 also influenced the ability of Akt inhibitors to Akt1 overexpression and gene amplification [222]. Abedini
potentiate cisplatin sensitivity. Ectopic expression of the et al. demonstrated that Akt confers cisplatin resistance via
tumor suppressor PTEN which inhibits PI3K/Akt pathway inhibition of p53-dependent ubiquitination and degradation
sensitized cisplatin-resistant ovarian cancer 2008/C13∗ cells of FLIP in response to cisplatin [223]. Claerhout et al. raised
the possibility that autophagy plays an important role in Cancer Institute. S. Krishnamurthy is supported by the
contributing to cisplatin resistance [224]. In a progressive Predoctoral Traineeship Award BC083099 from DOD BCRP.
model of cutaneous squamous cell carcinoma cell lines,
inhibition of autophagy by 3-methyladenine or by ATG5
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Review Article: Cellular Responses To Cisplatin-Induced DNA Damage

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Alakananda Basu and Soumya Krishnamurthy

Correspondence should be addressed to Alakananda Basu, [email protected]

Received 12 May 2010; Accepted 28 June 2010

Academic Editor: Ashis Basu

1. Introduction The success of cisplatin therapy is compromised due to

6.2. c-Abl and Cisplatin-Induced DNA Damage Response.

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