Elucidating the beneficial effects of melphalan, adriamycin, and corticoids in combination with bortezomib against multiple myeloma in vitro.

Combining bortezomib with other anti-cancer drugs or glucocorticoids is more efficient in multiple myeloma than bortezomib alone. However, the molecular mechanism of this beneficial effect is largely unknown. To investigate the effects of these compounds on bortezomib's anti-proliferative potency and its intracellular accumulation and potency to inhibit the chymotrypsin-like proteasomal subunit, seven myeloma cell lines were investigated after exposure to bortezomib alone or either combined with adriamycin plus dexamethasone (PAD regimen) or melphalan plus prednisolone (VMP regimen), respectively. PAD or VMP combinations did not alter cellular bortezomib uptake. However, PAD and VMP regimens increased bortezomib's chymotrypsin-like subunit inhibitory potency. This likely originates from indirect proteasome modulation, because adriamycin, dexamethasone, melphalan, or prednisolone did not inhibit this subunit when used alone. Strikingly, the anti-proliferative potency of bortezomib was not enhanced but slightly lowered in some cell lines when used in combinations. Adriamycin, dexamethasone, melphalan, or prednisolone can enhance bortezomib's chymotrypsin-like subunit inhibitory potency, likely by mechanisms indirectly influencing proteasome functionality.