Abstract
We have previously demonstrated that activation of the cyclic adenosine monophosphate (cAMP) pathway kills multiple myeloma (MM) cells both in vitro and in vivo. In the present study we have investigated the potential of enhancing the killing of MM cell lines and primary MM cells by combining the cAMP-elevating compound forskolin with the commonly used MM therapeutic drugs melphalan, cyclophosphamide, doxorubicin, bortezomib and dexamethasone. We observed that forskolin potentiated the killing induced by all the tested agents as compared to treatment with the single agents alone. In particular, forskolin had a synergistic effect on the dexamethasone-responsive cell lines H929 and OM-2. By knocking down the proapoptotic BCL-2 family member BIM, we proved this protein to be involved in the synergistic induction of apoptosis by dexamethasone and forskolin. The ability of forskolin to maintain the killing of MM cells even at lower concentrations of the conventional agents suggests that forskolin may be used to diminish treatment-associated side effects. Our findings support a potential role of forskolin in combination with current conventional agents in the treatment of MM.
Highlights
Inhibitors to inhibit cell proliferation and induce death of MM cells[13], our previous observations[8,10] indicate that cAMP-elevating agents such as forskolin might have a therapeutic potential in MM
In order to determine the effects of forskolin and the different therapeutic agents on death of human myeloma cell lines (HMCLs), incorporation of Propidium iodide (PI) was measured after 72 hours of treatment
We assessed the death of U266 and H929 cells treated with selected concentration of the DNA damaging agents melphalan, cyclophosphamide and doxorubicin as well as to the proteasome inhibitor bortezomib using ranges that are commonly applied in preclinical models[29,30,31,32]
Summary
Inhibitors to inhibit cell proliferation and induce death of MM cells[13], our previous observations[8,10] indicate that cAMP-elevating agents such as forskolin might have a therapeutic potential in MM. Forskolin is a diterpene produced by the roots of the Indian plant Coleus forskohlii[14]. Forskolin has been reported to modulate other cellular processes, such as ion channels[16,17], our previous studies have demonstrated that it induces MM cell death solely through elevation of cAMP levels[8,10]. We have investigated the effect of forskolin in MM cells in combination with clinically relevant MM therapeutic agents: DNA-damaging agents including the anthracycline antibiotic doxorubicin, the alkylating agent cyclophosphamide and melphalan, the proteasome inhibitor bortezomib, and the glucocorticoid dexamethasone. Taken into account the adverse side effects of current MM therapeutic agents, we propose forskolin as an adjuvant in combination with dexamethasone to reduce the side effects and increase the efficiency of MM treatments
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