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, 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 Cisplatin was discovered fortuitously by Dr. Rosenberg in 1965 while he was examining the effect of electromagnetic field on bacterial cell growth [1, 2]. Since the active principle that inhibited bacterial cell division was identified to be cisplatin, he anticipated that it would also inhibit the proliferation of rapidly dividing cancer cells. Cisplatin was indeed demonstrated to possess antitumor activity in a mouse model [3] and was first used in the clinical trial almost 30 years ago. Since its approval by the Food and Drug administration in 1978, cisplatin continues to be one of the most effective anticancer drugs used in the treatment of solid tumors. Cisplatin has been used as a first-line therapy for several cancers, including testicular, ovarian, cervical, head, and neck and small-cell lung cancers either alone or in combination with other anticancer agents. It is also used as an adjuvant therapy following surgery or radiation. In addition to cisplatin, its analogs, such as carboplatin and oxaliplatin, are also currently being used in the clinic. However, patients who initially respond to cisplatin therapy often develop resistance to the drug during the course of the treatment. The success of cisplatin therapy is compromised due to dose-limiting toxicity, especially nephrotoxicity as well as resistance by tumor cells to cisplatin. Cellular resistance to cisplatin could be either intrinsic or acquired. The clinically acquired resistance can be caused by decreased drug accumulation which includes reduced uptake or increased efflux of cisplatin, increased drug detoxification by cellular thiols, increased DNA repair or tolerance of cisplatin-damaged DNA and the ability of the cancer cells to evade cisplatininduced cell death. Numerous studies have focused on the drug-target interactions, cellular pharmacology, and pharmacokinetics of cisplatin. Another active area of research has been to develop analogs of cisplatin to minimize toxicity and circumvent cisplatin resistance. The antitumor activity of cisplatin is believed to be due to its interaction with chromosomal DNA [4]. Only a small fraction of cisplatin, however, actually interacts with DNA and the inhibition of DNA replication cannot solely account for its biological activity [5]. In addition, the efficacy of chemotherapeutic drugs depends not only on their ability to induce DNA damage but also on the cell’s ability to detect and respond to DNA damage [6]. Following DNA damage, cells may either repair the damage and start 2 progressing through the cell cycle or if they cannot repair the damage, cells proceed to die [5]. Cisplatin, like many other chemotherapeutic drugs, can induce apoptosis. Thus, the signaling pathways that regulate apoptosis have significant impact on deciding cellular responsiveness to cisplatin. There are many excellent reviews on cisplatin and its analogues [7– 15]. In this paper, we primarily focused on recent studies on cellular responses to cisplatin-induced DNA damage although we briefly discussed steps leading to cisplatininduced DNA damage. This comprehensive paper should not only benefit researchers in the field of cisplatin but also benefit those interested in mechanisms of chemoresistance and targeted therapy. 2. Biotransformation of Cisplatin Cisplatin or cis-diamminedichloroplatinum(II) is a neutral, square-planar, coordination complex of divalent Pt [8]. The cis configuration is required for its antitumor activity [16]. It has two labile chloride groups and two relatively inert amine ligands. Cisplatin undergoes hydrolysis in water. The chloride concentration is an important factor in determining the hydrolysis or aquation of cisplatin. The high chloride concentration (∼103 mM) of blood plasma prevents the 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 potent electrophile and reacts with a variety of nucleophiles, including nucleic acids and sulfhydryl groups of proteins. 3. Accumulation of Cisplatin Inside Cells Cisplatin and its analogues were initially thought to enter cells by passive diffusion because cisplatin uptake was linear, nonsaturable and could not be competed with platinum analogs [4–6, 17]. Although decreased accumulation of cisplatin is often associated with acquired resistance to cisplatin, few or no changes were observed in the plasma membrane function in the cisplatin-resistant cell lines as compared to the parental cells [18–20]. In 1981, it was first proposed that cisplatin could be transported actively via the carrier-mediated transport [21]. Several transporters, 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 membrane copper transporter-1 (CTR1), a member of the SLC family, gained particular attention since a defect in Ctr1 gene decreased cisplatin accumulation in yeast [23, 24]. In addition, cisplatin and carboplatin accumulation was attenuated in mouse embryonic fibroblasts from ctr1−/− animals compared to wild-type animals [18]. Interestingly, bot (...truncated)