Cisplatin, apoptosis induction

Zaffaroni N, Silvestrini R, Orlandi L, Bearzatto A, Gornati D, Villa R. Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and -resistant human ovarian cells. BrJ Cancer 1998 77(9) 1378-1385. 

The cyclin-dependent kinase inhibitor p21 is another downstream effector of p53 [161-163], There is evidence for p53-independent induction of p21 [162], and under these conditions the protein may be responsible for cisplatin-induced apoptosis [210][211], The p21 protein usually plays a protective role in response to cisplatin [212] [213], however, an effect which correlated with enhanced repair of a damaged reporter plasmid [212-214], These observations are consistent with the hypothesis that DNA-damage induced p53 activates a G, cell cycle arrest through p21, affording the cell time to repair the lesions and precluding the genetic instability produced by replication of damaged DNA. In accord with this model, the addition of p21 to cell free extracts blocked DNA replication but not excision repair... 

The toxicity is thought to be related to other heavy metal renal toxicity. In spite of the clinical importance and the relative frequency of this toxicity the mechanism of the toxicity remains unknown. A number of hypotheses have been put forward including altered mitochondrial function, activation of cisplatin, and inappropriate cellular binding, concentration of the heavy metal in the kidney, induction of apoptosis in... 

Although the PI3-K/Akt pathway is a promoter of cell proliferation and cell survival, under defined conditions, the PI3-K/Akt pathway is also involved in promoting cell death. The activation of PI3-K/Akt has been observed in some experimental systems on induction of apoptosis by selected stimuli like CD95, cisplatin, arsenite, TNF, serum withdrawal, hypoxia (Aki et al. 2001, 2003 Bar et al. 2005 Lee et al. 2005 Lu et al. 2006 Nimbalkar et al. 2003 Ono et al. 2004 Shack et al. 2003). Recent data also indicate that apoptin, a viral protein that selectively kills cancer cells, requires for its toxicity both PI3-K/Akt activation and the phosphorylation by CDK2 (Maddika et al. 2008a). 

D. (2007) IP3 receptor antagonist, 2-APB, attenuates cisplatin induced Ca +-influx in HeLa-S3 cells and prevents activation of cal-pain and induction of apoptosis. Brit J Pharmacol, 151, 1176-1186. 

Roth J. Modification of tumor suppressor gene expression and induction of apoptosis in non- small cell lung cancer (NSCLC) with an adenovirus vector expressing wildtype p53 and cisplatin. Hum Gene Ther 1996 7 1013-1030. 

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