Background and purpose: Although bortezomib has become one of the major therapeutic agents against newly diagnosed or relapsed multiple myeloma (MM)

there are some patients who become resistant to bortezomib and then relapse

emerging as a major obstacle to long-term survival of MM patients. It has been found that elevation of intracellular cyclic adenosine monophosphate (cAMP) levels could induce cell cycle arrest and apoptosis in MM cells，which has become an interesting approach to MM therapy. This study aimed to investigate possible effects of forskolin combined with bortez

omib on bortezomib-resistant myeloma cells and further explore its mechanisms. Methods: The bortezomib-resistant MM cell lines H929-R and primary cells from patients who do not respond to bortezomib were used as in vitro models. The influences of bortezomib and/or forskolin on MM cells were evaluated through cellular morphology

changes of cell distribution and apoptotic rate. Meanwhile

flow cytometry analysis was used to detect mitochondrial transmembrane potential (Δ

Ψm

) and the expression levels of apoptosis regulators in these cells before and after the treatment were detected by Western blot. Results: Bortezomib (20 nmol/L) synergized with forskolin (50 nmol/L) to induce apoptosis of H929-R cells and bortezomib-resistant primary cells. In addition

bortezomib synergized with forskolin to induce collapse of mitochondrial transmembrane and facilitate the degradation of anti-apoptosis proteins including Bcl-2 and Mcl-1. Conclusion: Bortezomib could synergize with forskolin to induce apoptosis in bortezomib-resistant MM cells.