Aspirin enhances the cytotoxic activity of bortezomib against myeloma cells via suppression of Bcl-2, survivin and phosphorylation of AKT

Abstract

In our previous study, it was found that aspirin (ASA) exerted antimyeloma actions in vivo and in vitro. The resistance to bortezomib (BTZ) in multiple myeloma (MM) is partly due to AKT activation and the upregulation of survivin induced by BTZ, which are the targets of ASA in gastric and ovarian cancer, respectively. Thus, the present study investigated the interaction between ASA and BTZ in MM and further clarified the underlying mechanisms. MM1.S and RPMI-8226 cell lines harboring the N- and K-Ras mutations, respectively, were treated with 2.5 mM ASA, 10 nM BTZ and ASA+BTZ for different durations. The proliferation and apoptosis of the cells were determined, and the underlying mechanisms governing the interaction of ASA and BTZ were examined in the MM cells. Treatment with ASA+BTZ caused higher rates of proliferative inhibition and apoptosis in the MM1.S and RPMI-8226 cells in time-dependent manner, compared with either agent alone. A drug interaction assay revealed the additive effect of ASA and BTZ on the myeloma cells. ASA alone inhibited the levels of phosphorylated AKT (p-AKT) and survivin, whereas BTZ alone augmented the levels of p-AKT and survivin. Of note, ASA markedly decreased the upregulation of p-AKT and survivin induced by BTZ. Treatment with ASA+BTZ significantly suppressed the level of Bcl-2, compared with either agent alone. 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.

ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy

“…It is well known that the AKT pathway has an important role in regulating human cancer cell survival 38 . Dysregulation of the AKT pathway can be observed in cancers, which may be involved in the resistance mechanisms of tumor cells 15,38 . Phosphorylation of AKT can activate the serine/threonine kinase mTOR that acts as an important upstream regulator of autophagy 24 .…”

Translational impact of novel widely pharmacological characterized mofezolac-derived COX-1 inhibitors combined with bortezomib on human multiple myeloma cell lines viability

“…Nearly all MM patients experience relapse and refractory disease [23]. Aspirin use, along with reducing the incidence of thrombotic complications also improves overall survival, by producing additive or synergistic effects in the treatment of MM because enhances bortezomib cytotoxicity via suppression of Bcl-2, survivin and AKT phosphorylation [24].…”

Soluble and Cell–Cell-Mediated Drivers of Proteasome Inhibitor Resistance in Multiple Myeloma

“…Akt can be activated by numerous agents (cytokines, integrins, RTKs, BCR signaling, and GPCR ligands) and can be downstream of the Jak1 and PI3K pathways. Recent studies in myeloma cells with N- and K-Ras mutations suggest that aspirin can increase the efficacy of bortezomib treatment via suppression of Akt phosphorylation, upregulation of survivin, and in part through suppressing Bcl-2 levels ( 45 ). The allosteric AKT inhibitor MK2206 was also found in myeloma cells to overcome bortezomib resistance induced by IL-6 or MSCs ( 46 ).…”