The pan-BH-3 mimetic, obatoclax, synergistically enhances cisplatin-induced apoptosis in oral squamous cell carcinoma through a mechanism that involves degradation of the pro-survival protein Mcl-1

Abstract

Objectives

The purpose of the study was to elucidate the role of the Bcl-2 family of proteins in mediating cisplatin resistance in oral squamous cell carcinoma (OSCC). The value of the BH3-mimetics venetoclax and obatoclax as sensitisers for cisplatin treatment in OSCC was also evaluated.

Design

In this study the expression levels of a series of pro- and anti-apoptotic members of the Bcl-2 family in paired cisplatin-sensitive (SCC4) and resistant (SCC4cisR) tongue squamous carcinoma cell lines were examined by western blotting. The apoptotic rate induced by cisplatin and BH3-mimetics venetoclax and obatoclax alone or in combination in OSCC was also evaluated by Annexin V/Propidium Iodide double-stained flow cytometric assays.

Results

Obatoclax was shown to synergistically enhance cisplatin-induced apoptosis, and this enhancement was associated with a marked degradation in pro-survival Mcl-1 and upregulation in conformationally active form of pro-apoptotic Bak.

Conclusions

Our study presents novel insights into the relationship between the Bcl-2 family and cisplatin efficacy in OSCC. It also demonstrates that targeted therapy with BH-3 mimetics, such as obatoclax, may represent a new strategy for OSCC therapy.