The proteasome inhibitor MLN9708 is an orally administered drug that is hydrolyzed into its active form, MLN2238 (ixazomib). Compared with Bortezomib, MLN2238 has a shorter proteasome dissociation half-life and a lower incidence and severity of peripheral neuropathy, which makes it an attractive candidate for colorectal cancer treatment. In the present study, we observed that MLN2238 induced autophagy, as evidenced by conversion of the autophagosomal marker LC3 from LC3I to LC3II, in colorectal cancer cell lines. Mcl-1, an anti-apoptotic Bcl-2 family protein, was markedly elevated after treating a colorectal cancer cell line with MLN2238. We proved that inhibiting Mcl-1 expression enhances MLN2238 induced apoptosis and negatively regulates autophagy. Co-administration of BH3 mimetic ABT-737 with MLN2238 synergistically kills colorectal cancer cells through MCL-1 neutralization and autophagy inhibition. Furthermore, the synergistic killing effect of the combination therapy is correlated with P53 status in colorectal cancer. These data highlight that the combination of ABT-737 with MLN9708 is a promising therapeutic strategy for human colorectal cancer.
[1]Fudan Univ, Shanghai Canc Ctr, Dept Radiat Oncol, Shanghai 200032, Peoples R China.
[2]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China.
[3]Fudan Univ, Shanghai Med Coll, Inst Brain Sci, Dept Integrat Med & Neurobiol,Inst Acupuncture Re, Shanghai 200032, Peoples R China.
[4]Thomas Jefferson Univ, Dept Radiat Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA.
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