Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis

Abstract

Ovarian cancer is the leading cause of death from gynecological cancer. The anti-apoptotic protein Bcl-x(L) is frequently overexpressed in ovarian carcinoma which correlates with chemotherapy resistance. It has been demonstrated that Bcl-x(L) cooperates with another anti-apoptotic protein, Mcl-1, to protect ovarian cancer cells against apoptosis, and that their concomitant inhibition induces massive cell death. Here, we examined the interest of ABT-737, a potent BH3-mimetic molecule targeting Bcl-x(L), both alone and in combination with Mcl-1 modulators, in ovarian cancer cell lines. As a single agent, ABT-737 was ineffective at promoting cell death in the four cell lines we tested in vitro. However, the specific inhibition of Mcl-1 by siRNA dramatically increased the sensitivity of chemoresistant cells to ABT-737. Platinum compounds also sensitize to ABT-737 by dose-dependently decreasing Mcl-1 expression or by increasing the expression of pro-apoptotic BH3-only proteins Noxa and, to a lower extent, Bim. Furthermore, we demonstrated that Noxa accumulation was involved in apoptosis occurring in response to the combination of ABT-737 and platinum compounds, since cells were protected from apoptosis by its silencing. Moreover, the combination was also highly cytotoxic ex vivo in sliced SKOV3 tumor nodes. However we observed in these slices a strong basal expression of Noxa and apoptotic cell death in response to ABT-737 alone. Therefore, we have revealed that the modulation of the Mcl-1/Noxa axis by platinum compounds results in a strong sensitization of chemoresistant ovarian carcinoma cells to ABT-737, which could constitute a promising therapeutic in these cancers.

Bcl2L12 with a BH3-like domain in regulating apoptosis and TMZ-induced autophagy: A prospective combination of ABT-737 and TMZ for treating glioma

“…However, we found that TMZ can decrease the expression Mcl-1 (data not shown), which alternatively created a good environment for ABT-737 to take action without interfering. The extent of the high Mcl-1 expression would restrict the therapeutic effect of ABT-737 as described (43). Likewise, siRNA-based knock down Mcl-1 expression or implicated pharmaceutical-based (using platinum agent) drug all improved ABT-737 resistance; ii) ABT-737 as BH3 mimetic agent, may be suitable to counteract an anti-apoptotic role of Bcl2L12 in glioma that retains an acquired resistance to TMZ.…”

The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737

“…ABT-737, one of the most potent BH3-mimetic compounds, binds with high affinity to the hydrophobic groove of Bcl-2, Bcl-x L , and Bcl-w and antagonizes their antiapoptotic function (12). It induces apoptosis in several cellular models (12)(13)(14) and sensitizes ovarian cancer cells to platinum compounds (7). Its orally available form, ABT-263 (navitoclax), is currently undergoing phase II clinical evaluation as a single agent in various tumor types, including ovarian tumors (http://www.clinicaltrials.gov NCT02591095).…”

High BIM mRNA levels are associated with longer survival in advanced gastric cancer

“…Platinum-resistant cancer cells conserved sensitivity to BH3-induced mitochondrial apoptosis (16). In line with that, BH3-mimetic compounds such as ABT-737 were able to sensitize cancer cells to platinum (17). In addition, overexpression of BIM enhanced the in vitro sensitivity to docetaxel of non-small cell lung cancer (NSCLC) (18).…”