Exploring The Combination Treatment For Multiple Myeloma And The Potential Mechanisms

Multiple myeloma(MM)is a progressive and incurable clonal plasma cell neoplasm involving the bone marrow and extramedullary sites.The incidence of MM has increased significantly in recent decades.Combination chemotherapy is the maily treatment for this disease,while the front-line clinic drugs(proteasome inhibitor bortezomib and immune modulator lenalidomide)remain unsatisfacting outcomes due to the drug tolerance of patients,drug resistance and side effects.Thus,relapses often occur.Moreover,bortezomib is not effective in refractory cases or relapsed MM patients.Therefore,it is important to find effective treatment that can overcome drug resistance and reduce side-effects.BKM120 is a potent pan-PI3 K inhibitor mainly used against solid tumors in phase II clinical trails.It is reported that PI3K/AKT signaling pathway plays an important role in the progress of bortezomib resistance.Therefore,we treated multiple myeloma with BKM120 in combination with bortezomib to explore whether BKM120 overcomes bortezomib resistance and advances the anti-tumor effect of bortezomib.This work mainly achieved the following results:(1)PI3K/AKT signaling pathway plays an important role in bortezomib resistance.We validated that bortezomib activates PI3K/AKT signgaling pathway and the basic activity of this pathwaiy is obviously higher in bortezomib-resistant MM cells than in bortezomib-sensitive cells.(2)BKM120 enhances the anti-tumor effect of bortezomib by inducing more cell apoptosis both in bortezomib-resistant and bortezomib-sensitive cells.(3)BKM120 advances the anti-tumor effect of bortezomib by inhibition of PI3K/AKT pathway.(4)The combination treatment of BKM120 and bortezomib also performs advanced anti-tumor effects in MM mouse model and primary MM cells.Montelukast(MK-0476),a selective reversible cys-leukotriene-1 receptor(LTD4 receptor)antagonist is used in the treatment of asthma.Leukotrienes(LTs)are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid via a 5-lipooxygenase(5-LOX)pathway(Wenzel,1998).It is reported that 5-LOX is expressed by a wide variety of tumor cells and tissues.Therefore,LTs maybe potential targets in the treatment of malignancies.Based on these reports,we performed experiments in multiple myeloma cells to explore its effect and the potential mechanism.This work mainly achieved the following results:(1)Montelukast inhibits multiple myeloma cell growth and induces apoptosis which is synergistic with carfilzomib;(2)The combination treatment induces obviously cell apoptosis by activating ER stress;(3)The combination treatment obviously induces the accumulation of ubiquitination,which is independent of the inhibition of LTD4 receptor;(4)Montelukast is synergistic with carfilzomib in multiple myeloma by inhibiting the deubiquitinase UCHL1.