Camptothecin sensitizes androgen-independent prostate cancer cells to anti-Fas-induced apoptosis

Abstract

Despite expressing both Fas and Fas ligand, DU145 and LNCaP prostate cancer cells were resistant to anti-Fas-induced cell death. Resistance to Fas-mediated cytotoxicity could be overcome in DU145, but not in LNCaP, cells by pretreating cells with sublethal doses of cytotoxic drugs, such as camptothecin. Activated caspases were shown to be required for this cytotoxicity. Indeed, poly(ADP-Ribose) polymerase was shown to be proteolytically cleaved in cells treated with camptothecin plus anti-Fas, but not in cells treated with anti-Fas only. Moreover, pretreatment of cells with ZVAD completely blocked camptothecin-mediated Fas-induced apoptosis. Sensitization of cells to Fas-induced cell death did not involve up-regulation of Fas or FasL, and it was independent of alterations in the cell cycle. Reactive oxygen intermediates (ROI) have been shown to be important mediators of drug-induced apoptosis. Here, we demonstrate that treatment of DU145 cells with camptothecin, anti-Fas, or both, did not alter the intracellular levels of peroxide or superoxide anion. © 1999 Cancer Research Campaign

Activation of SAPK/JNK by camptothecin sensitizes androgen-independent prostate cancer cells to Fas-induced apoptosis

“…DU145 cells express both Fas and FasL, but are resistant to anti-Fas-mediated apoptosis, unless pretreated with sublethal doses of a cytotoxic drug, such as camptothecin (Costa-Pereira and Cotter, 1999). Here, we show that treatment of DU145 prostate cancer cells with anti-Fas failed to activate SAPK/JNK.…”

“…We have previously shown that activated caspases were required for this cytotoxicity (Costa-Pereira and Cotter, 1999). However, inhibition of caspase activity by the pan-inhibitor z-VAD had no effect on SAPK/JNK activation following concomitant treatment of cells with camptothecin and anti-Fas, suggesting that SAPK/JNK activation was not caspase-dependent.…”

“…Although DU145 cells are resistant to anti-Fas-mediated cytotoxicity, the cells retain the cellular components of the apoptotic machinery necessary to undergo death triggered by Fas, as the resistance can be overcome by pretreating the cells with sublethal doses of camptothecin. This effect is independent of receptor expression, as levels were the same in resistant and sensitized cells (Costa-Pereira and Cotter, 1999). Other cytotoxic drugs (e.g.…”

“…The concept of a 'Fas counterattack' has emerged as a possible mechanism used by tumours to escape immune surveillance (O'Connell et al, 1996;Villunger et al, 1997). Recently, it has been shown that the normal epithelium, as well as locally invasive prostate cancers, have the potential to undergo Fas-induced apoptosis, whereas metastatic prostate cancers have a reduced susceptibility to Fas-mediated apoptosis (Hedlund et al, 1998;Costa-Pereira and Cotter, 1999).…”

Molecular and cellular biology of prostate cancer—the role of apoptosis as a target for therapy

“…193 In addition, we have recently shown that a combinatory treatment of androgen-independent DU145 cells with sublethal concentrations of camptothecin and very low concentrations of anti-Fas IgM, will kill 75 ± 95% of a cell culture population in 24 h. 194 Fas (CD95aAPO-1) belongs to the nerve growth factoratumour necrosis factor (NGFaTNF) receptor family, and its main function is the induction of apoptosis in a variety of cell types. 195,196 The prostatic epithelium is one of the few tissues to co-express Fas and FasL, along with other immune privileged tissues which are marked by apoptotic turnover, and there is evidence for an in vivo role for Fas signalling in the hormonal regulation of the normal, differentiated prostatic epithelium.…”