Antiproliferative and Proapoptotic Effect of Vitamin D in Bortezomib (B) Resistant Human Myeloma Cell Line (HMCL).

-Introduction: B is a proteasome inhibitor approved for treatment of multiple myeloma (MM) patients. Despite initial clinical efficacy all patients eventually become resistant to bortezomib and die of progressive disease. Development of newer agents with novel antitumor mechanisms is thus warranted. In vitro antiproliferative and proapoptotic effects of vitamin D are reported in various tumor models including MM. This is mediated through vitamin D receptor (VDR) which is also expressed on MM cells. Effect of calcitriol (D₃) or its analog paricalcitol (D₂) in HMCL resistant to B have not been previously examined. We investigated the antitumor potential of D₃ and D₂ in HMCL sensitive or resistant to B.

Method & Results: HMCL sensitive (OPM-2) or resistant to B (OPM-2/BR) were treated with various concentration of D₂ or D₃. Significant growth inhibition and induction of apoptosis was noted with D₂ and D₃ that was maximal at 3 days (p<0.01). This antitumor response was noted despite resistance to B. Treatment of MM cells with vitamin D (D₂ or D₃) was associated with a loss of full-length PARP, decrease in p21 and induction of p27. Levels of the pro-survival molecules P-Akt and P-Erk were also reduced while total Akt and Erk remain unchanged.

Conclusion: We demonstrate that the antiproliferative and proapoptotitc effect of vitamin D in HMCL are mediated through interruption of the Akt pathway and were independent of resistance to B. We have initiated a phase I clinical trial to investigate the clinical utility of paricalcitol in relapsed or refractory MM patients.