Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions

抄録

Myeloma (MM) cells and osteoclasts create a highly acidic milieu in MM bone lesions by proton produced by osteoclasts and lactate by MM cells. Although bendamustine exerts clinical activity against MM, the potential mechanisms of action of bendamustine remain largely unknown. In the present study, we therefore explored anti-MM activity of bendamustine with special reference to its effects on MM cells in acidic conditions. Bendamustine at the range of 25 to 100 μM dose-dependently induced death in INA6 and TSPC-1 MM cells. However, bendamustine did not impair the viability of RPMI8226, U266 and OPC cells even at 100 μM. In acidic conditions at pH 6.8 or lower, the bendamustine’s cytotoxic effects were further enhanced in INA6 and TSPC-1 cells, and triggered in RPMI8226 and MM.1S cells which were resistant to bendamustine at pH 7.4. Intriguingly, bendamustine reduced Pim-2 protein levels in MM cells and enhanced its anti-MM activity in combination with the Pim inhibitor SMI-16a, preferentially in acidic conditions. These results demonstrate that anti-MM effects of bendamustine are augmented in acidic conditions, but considerably vary among MM cells, and that Pim inhibition further enhances the bendamustine’s anti-MM activity in acidic conditions.