ABT-737 is a small molecule kinase inhibitor that has shown preclinical anticancer activity against many types of cancers.  ABT-737 mimics the direct binding to the hydrophobic groove in Bcl-2, Bcl-xL, and Bcl-w and consequently prevents them from sequestering proapoptotic BH3-only proteins such as tBid, Bad, and Bim. However, ABT-737 binds with lower affinity to the Bcl-B, Mcl-1, and Bfl-1/A1 proteins.Given that ABT-737 binds to Mcl-1 with low affinity, the high basal expressions of Mcl-1 in small-cell lung cancer cells  and in other types of cancer cells have been validated to associate with the resistance to ABT-737. In our study, we showed that gemcitabine and ABT-737 in combination had substantial synergistic antitumor efficacy against human cancer cells both in vitro and in vivo.

We determined the cytotoxicity of gemcitabine and ABT-737 at clinically achievable concentrations ranging from 0.5 to 4 µmol/L in 6 human carcinoma cell lines by using the MTT cytotoxicity assay. Gemcitabine plus ABT-737 induced apoptosis and depolarization of mitochondrial membrane potential. We further observed that treatment of cells with gemcitabine plus ABT-737 for 24 hours caused a significantly greater activation of procaspase-3 than did either agent used alone. Gemcitabine combined with ABT-737 abolished the interaction between Mcl-1 and Bax.The ubiquitin–proteasome system was activated by the combination of gemcitabine and ABT-737. Increased Mcl-1 levels led to resistance to ABT-737. Gemcitabine disrupted the enhanced interaction of USP9X and Mcl-1 by ABT-737. RNA interference of Mcl-1 and USP9X sensitized cells to combination gemcitabine and ABT-737 treatment. Mcl-1 depletion increased gemcitabine plus ABT-737–induced apoptosis. USP9X knockdown amplified the apoptosis induced by gemcitabine and ABT-737. The combination of gemcitabine and ABT-737 arrested tumor growth.The combination therapy induced apoptosis and downregulated Mcl-1 in tumor tissues.

In conclusion, we present evidence showing better therapeutic activity of gemcitabine when combined with bcl-2 inhibitor ABT-737 both in vitro and in vivo. Our results also show that gemcitabine plus ABT-737 combination treatment synergistically induced caspase-dependent apoptosis via disrupting the interaction between USP9X and Mcl-1. Therefore, a combination chemotherapy regimen incorporating a small-molecule BH3-mimetic with gemcitabine warrants clinical investigation in solid tumors.

Reference:

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1
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