ASA may potentiate the antimyeloma activity of BTZ against myeloma cells via suppression of AKT phosphorylation, survivin and Bcl-2, indicating the potential of ASA+BTZ in treating MM, particularly for cases of BTZ-refractory/relapsed MM.
We used the Bcl-2/Bcl-x<sub>L</sub> inhibitor ABT-737 to study the factors regulating whether myeloma is Mcl-1 dependent, and thus resistant to ABT-737-induced apoptosis, or Bcl-2/Bcl-x<sub>L</sub> codependent, and thus sensitive to ABT-737.
Moreover, miR-324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes.
Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone.
ABT-199 is a specific Bcl-2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co-expression of Mcl-1 and Bcl-xL.
This review addresses the role and regulation of pro-survival BCL-2 family proteins during healthy PC differentiation and in MM, as well as their potential as therapeutic targets.
Approximately, 20% of myeloma patients will exhibit <i>t</i> (11;14) associated with high BCL-2 expression making venetoclax an attractive therapeutic option.
In myeloma, in vitro sensitivity to venetoclax is mainly observed in plasma cells harboring the t(11;14) translocation, a molecular subgroup associated with high Bcl-2 and low Mcl-1/Bcl-XL expression.
Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions.
Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2.
Taken together, miR‑497 suppressed MM cell proliferation and promoted apoptosis by directly targeting Bcl‑2 and altering the expression of downstream apoptosis‑related proteins.
Co-culture experiments resulted in MDSC-induced AMPK phosphorylation in MM cells, which was associated with an increase in the anti-apoptotic factors MCL-1 and BCL-2, and the autophagy-marker LC3II.