MINIREVIEW Is Cisplatin-Induced Cell Death Always Produced by Apoptosis? VICTOR M. GONZALEZ, MIGUEL A. FUERTES, CARLOS ALONSO, and JOSE M. PEREZ Departamento de Bioquı´mica y Biologı´a Molecular, Facultad de Medicina, Universidad de Alcala ´ , Alcala ´ de Henares, Madrid, Spain (V.M.G.); Centro de Biologı´a Molecular “Severo Ochoa” (CSIC-UAM), Facultad de Ciencias, Universidad Auto ´ noma de Madrid, Cantoblanco, Madrid, Spain (M.A.F., C.A.); and Departamento de Quı´mica Inorganica, Facultad de Ciencias, Universidad Auto ´ noma de Madrid, Cantoblanco, Madrid, Spain (J.M.P.) Received August 7, 2000; accepted January 16, 2001 This paper is available online at http://molpharm.aspetjournals.org The platinum drugs represent a unique and important class of antitumor agents. The clinical development of the neutral, square planar, coordination complex cis-diam- minedichloroplatinum(II) (cisplatin), marked in the 1970s a watershed in the treatment of cancer. Cisplatin is widely used for the treatment of many malignancies, including tes- ticular, ovarian, bladder, cervical, head and neck, and small- cell and non–small-cell lung cancers (Rosenberg, 1999). The cisplatin analog 1,1-cyclobutanedicarboxylate platinum(II) (carboplatin), has also been used increasingly in the last 2 decades. Despite the great efficacy at treating certain kinds of cancers, cisplatin, carboplatin, and other cisplatin analogs introduced into clinics have major problems, such as several side effects and the acquisition or presence of resistance to these drugs that undermines their curative potential (Kelland, 1993). Thus, considerable efforts are being directed toward the development of novel platinum compounds with clinical profiles complementary to that of cisplatin and its analogs, such as trans-Pt(II) compounds, Pt(IV) compounds, and polynuclear platinum compounds (Wong and Giando- menico, 1999; Pe ´rez et al., 2000). Cisplatin is a well known DNA-damaging agent and the current thinking is that DNA plastination is an essential first step in the cytotoxic activity of the drug. However, the mechanism(s) whereby these DNA adducts kill cells is not fully understood. One potentially important way by which cisplatin-DNA adducts may kill cells is by induction of pro- grammed cell death or apoptosis (Eastman, 1999). Is cispla- tin-induced cell death always the result of an apoptotic path- way? This review tries to shed light on this important issue. Molecular and Cellular Pharmacology of Cisplatin Intracellular Accumulation. Cisplatin cellular uptake is barely understood. The current data indicate that cisplatin enters cells through transmembrane channels but these data are also consistent with high-capacity facilitated transport (Gately and Howell, 1993). So far, the search for a specific cisplatin membrane transport system has been unsuccessful. Once cisplatin enters the cell, the chloride concentration drops to  20 mM and the drug undergoes strong hydration to form positively charged active species for subsequent in- teraction with cellular nucleophiles (Andrews and Howell, 1990). Binding to DNA and Other Cellular Targets. Many cellular components that have nucleophilic sites such as DNA, RNA, proteins, membrane phospholipids, cytoskeletal microfilaments, and thiol-containing molecules react with cisplatin, although only approximately 1% of the intracellu- lar cisplatin reacts with nuclear DNA to yield a variety of adducts that include interstrand and intrastrand DNA cross- links and DNA-protein cross-links (Fig. 1). The most common adduct is an intrastrand cross-link between adjacent gua- nines (Pe ´rez, 1998). Although genomic DNA is generally ac- cepted as the critical pharmacological target of cisplatin- induced cytotoxicity, there is evidence that other cellular targets may also be involved in the cytotoxicity of the drug. Thus, cisplatin binds to mitochondrial DNA, interacts with phospholipids and phosphatidylserine in membranes, This work was supported by Spanish Comisio ´n Interministerial de Ciencia y Tecnologica (Grant BIO-99/1133). We also thank the European Cooperation in the Field of Scientific and Technical Research Network (COST D20/003/00 Action: “Biochemistry, Structural and Cellular Biology of NonClassical Anti- tumor Platinum Compounds”). An institutional grant from Fundacio ´n Ramo ´n Areces is also acknowledged. ABBREVIATIONS: cisplatin, cis-diamminedichloroplatinum(II); NER, nucleotide excision repair; MMR, mismatch repair; DNA-PK, DNA-dependent protein kinase; HMG, high-mobility group; caspase, cysteine aspartate-specific proteinase; transplatin, trans-diamminedichloroplatinum(II); DISC, death-inducing signaling complex; FasL, Fas ligand; bFGF, basic fibroblast growth factor. 0026-895X/01/5904-657–663$3.00 MOLECULAR PHARMACOLOGY Vol. 59, No. 4 Copyright © 2001 The American Society for Pharmacology and Experimental Therapeutics 471/898171 Mol Pharmacol 59:657–663, 2001 Printed in U.S.A. 657 at ASPET Journals on November 8, 2016 molpharm.aspetjournals.org Downloaded from