BACKGROUND: Aberrant overexpression of Bcl-2 protein has been detected in 80% of 
nasopharyngeal carcinoma (NPC), and Bcl-2 family proteins are implicated in both 
NPC oncogenesis and chemotherapy resistance. Previous studies have shown that 
while treatment of NPC cells with Bcl-2 family inhibitors alone is rarely 
effective, concomitant treatment with a cytotoxic reagent such as cisplatin can 
increase efficacy through a synergistic effect. The aim of the current work was 
to determine how we might increase the efficacy of Bcl-2 family inhibitors in 
the absence of cytotoxic reagents, which are associated with negative side 
effect profiles.
METHODS: We assessed cell proliferation in Bcl-2 high-expressing NPC cells by 
CCK-8 assay after treatment with the Bcl-2 inhibitor ABT-199 and/or the Mcl-1 
inhibitor S63845. Apoptotic induction by ABT-199 was evaluated by Annexin V-FITC 
and PI double staining. We also evaluated Bcl-2 family protein expression (Bim, 
Mcl-1, Bcl-xL, Noxa) after treatment with ABT-199 by western blotting. Finally, 
xenografted Balb/c nude mice were used to test ABT-199 efficacy in vivo, H&E and 
immunohistochemistry assay were used to analyze tumor samples.
RESULTS: ABT-199 effectively induced NPC cell apoptosis in vitro and in the 
xenograft model. Following ABT-199 treatment in NPC cells, upregulation of Mcl-1 
and Bcl-xL can lead to drug resistance, while concomitant Noxa overexpression 
partially neutralized the Mcl-1-caused resistance. Given that ABT-199 induces 
apoptosis in NPC cells through the Bcl-2/Noxa/Mcl-1 axis, treatment avenues 
further targeting this pathway should be promising. Indeed, the newly developed 
Mcl-1 inhibitor S63845 in combination with ABT-199 had a synergistic effect on 
NPC cell apoptosis.
CONCLUSION: Bcl-2 inhibition in NPC cells with ABT-199 triggers apoptosis 
through the Bcl-2/Noxa/Mcl-1 axis, and dual inhibition of the anti-apoptotic 
Bcl-2 family proteins Bcl-2 and Mcl-1 provided a strong synergistic effect 
without the need for adjunctive cytotoxic agent treatment with cisplatin.