Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo.
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.
Lin
Boris
B
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Catley
Laurence
L
LeBlanc
Richard
R
Mitsiades
Constantine
C
Burger
Renate
R
Tai
Yu-Tzu
YT
Podar
Klaus
K
Wartmann
Markus
M
Chauhan
Dharminder
D
Griffin
James D
JD
Anderson
Kenneth C
KC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple / Q000187:drug effects; D034261:Epothilones / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000473:pathology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D034261:Epothilones; D015850:Interleukin-6; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; C093788:epothilone B