A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer

Abstract

Platinum-based anticancer drugs, including cisplatin and carboplatin, have been cornerstones in the treatment of solid tumors. We report here that these DNA-damaging agents, particularly cisplatin, induce apoptosis through plasma membrane disruption, triggering FAS death receptor via mitochondrial (intrinsic) pathways. Our objectives were to: quantify the composition of membrane metabolites; and determine the potential involvement of acid sphingomyelinase (ASMase) in the FAS-mediated apoptosis in ovarian cancer after cisplatin treatment. The resulting analysis revealed enhanced apoptosis as measured by: increased phosphocholine, and glycerophosphocholine; elevated cellular energetics; and phosphocreatine and nucleoside triphosphate concentrations. The plasma membrane alterations were accompanied by increased ASMase activity, leading to the upregulation of FAS, FASL and related pro-apoptotic BAX and PUMA genes. Moreover FAS, FASL, BAX, PUMA, CASPASE-3 and -9 proteins were upregulated. Our findings implicate ASMase activity and the intrinsic pathways in cisplatin-mediated membrane demise, and contribute to our understanding of the mechanisms by which ovarian tumors may become resistant to cisplatin.

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

“…No caspase-3 in MCF-7 breast cancer cells indicates that apoptosis in these cells is activated by other transmitters in the suppressor protein p53, NF-kB or TNF-a [43][44][45] . In recent years, it has been found that cisplatin also can induce apoptosis by activates the extrinsic pathway activated by members of the tumor necrosis factor (TNF) super family such as FAS receptor 46 . FAS can trigger apoptosis through its FAS ligand (FASL), upon engagement of the FAS-associated death domain protein (FADD), and recruitment of procaspase-8 and procaspase-10 to the intracellular death domain of FAS receptor form the death-inducing signaling complex (DISC) that either directly initiates a downstream caspase cascade 47,48 .…”

Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers

“…We previously reported an increase in apoptosis in A2780 and A2780/C30 cells treated with cisplatin, 6 D2, and D4. 15 Consistent with these prior observations, exposure of A2780 cells to either 7 µM cisplatin, (used as a positive control) or phosphaplatin complexes (45 µM RRD4 or 180 µM RRD4) for 24 hrs resulted in a marked increase in apoptosis (2.5-, 3.2-, 5.9-fold, respectively; P<0.05), compared to untreated controls.…”

Cisplatin‐induced alteration on membrane composition of A549 cells revealed by ToF‐SIMS

“…In contrast, the large fragment ion arising from cholesterol at m/z 369.29 (C 27 H 45 + ) had a notable negative PC1 loading value, indicating higher abundance of cholesterol in A549/DDP cell membrane compared to A549 cell membrane. Cholesterol is a critical constituent of mammalian cell plasma membrane, which is vital in membrane stabilization, lipid raft formation, as well as receptor function . It has been reported that cisplatin accumulation was reduced in many resistant cell lines, which have rigid cell membranes with high‐cholesterol content .…”