ABT737 reverses cisplatin resistance by regulating ER-mitochondria Ca2+ signal transduction in human ovarian cancer cells

Abstract

Bcl-2, which belongs to the Bcl-2 family, is frequently overexpressed in various types of cancer cells and contributes to drug resistance. However, the function of Bcl-2 in cisplatin resistance in human ovarian cancer cells is not fully understood. In this study, we found that the pharmacological inhibitor ABT737 or genetic knockdown of Bcl-2 increased cisplatin cytotoxicity in cisplatin-resistant ovarian cancer cells. Additionally, treatment with ABT737 or Bcl-2 siRNA increased cisplatin-induced free Ca2+ levels in the cytosol and mitochondria, which increased endoplasmic reticulum (ER)-associated and mitochondria-mediated apoptosis. In addition, ABT737 or Bcl-2 siRNA increased the ER-mitochondria contact sites induced by cisplatin in cisplatin-resistant SKOV3/DDP ovarian cancer cells. Consistently with the in vitro results, ABT737 potently synergized with cisplatin in inhibiting the growth of human ovarian cancer xenografts in nude mice. Collectively, these results indicate that pharmacological inhibitors or genetic knockdown of Bcl-2 may be a potential strategy for improving cisplatin treatment of ovarian cancer.

The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca 2+ signaling

“…Indeed, while cisplatin by itself induces mitochondrial hyperfusion in cholangiocarcinoma cells, it induces mitochondrial fragmentation and mitophagy when co-applied with ABT-737 [48]. Moreover, in cisplatin-resistant ovarian cancer cells, ABT-737 can also promote the formation of ERmitochondrial contact sites induced by cisplatin, thereby augmenting cisplatin-induced Ca 2+ rise in the mitochondria and apoptosis [38]. These observations further underpin the intimate link between the effective response to anti-cancer therapeutics and efficient ER-mitochondrial Ca 2+ transfer [43,46,49].…”

“…Very interestingly, ABT-737, a non-selective Bcl-2/Bcl-XL inhibitor, can sensitize cholangiocarcinoma and ovarian cancer cells to cisplatin treatment via a mechanism that involves mitochondrial remodeling and Ca 2+ signaling [38,48]. Indeed, while cisplatin by itself induces mitochondrial hyperfusion in cholangiocarcinoma cells, it induces mitochondrial fragmentation and mitophagy when co-applied with ABT-737 [48].…”

“…In addition to this, we tested whether acute application of venetoclax is able to affect the mitochondrial Ca 2+ flux, since prolonged incubation of ovarian cancer cells with ABT-737, another BH3-mimetic drug, leads to alterations in ER-mitochondrial Ca 2+ signaling [38].…”

Endoplasmic Reticulum–Mitochondrial Ca2+ Fluxes Underlying Cancer Cell Survival

“…Interestingly, some anticancer drugs might actually impact ER–mitochondrial contact sites and thereby enhance the response to other chemotherapeutics. For instance, ABT-737, a non-selective Bcl-2/Bcl-XL inhibitor (114, 115) could reverse the cisplatin resistance in ovarian cancer cells due to increased ER–mitochondrial Ca 2+ contact sites (116). Specifically, the authors demonstrated that ABT-737 enriched cisplatin-induced GRP75 and Mfn-2 content at the ER–mitochondria interface.…”

“…Specifically, the authors demonstrated that ABT-737 enriched cisplatin-induced GRP75 and Mfn-2 content at the ER–mitochondria interface. The latter event led to enhanced mitochondrial Ca 2+ overload and subsequent cell death (116). Moreover, tumor suppressors at MAMs, including p53, were reported to modulate Ca 2+ transfer and the contact sites (54).…”