In this study, we investigated the in vitro and in vivo efficacy of
patupilone (
epothilone B,
EPO906), a novel nontaxane microtubule
stabilizing agent, in treatment of
multiple myeloma (MM).
Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional
chemotherapies, such as the
taxane paclitaxel.
Patupilone induced G2M arrest of MM cells, with subsequent apoptosis.
Interleukin-6 (IL-6) and
insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against
patupilone-induced cell death. Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by
patupilone and was paralleled by down-regulation of
vascular endothelial growth factor (
VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with
IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of
patupilone. Moreover,
patupilone was effective against MM cell lines that overexpress the MDR1/
P-glycoprotein multidrug efflux pump. In addition,
patupilone was effective in slowing
tumor growth and prolonging median survival of mice that received orthotopical transplants with MM
tumor cells. Taken together, these preclinical findings suggest that
patupilone may be a safe and effective
drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM.