The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo.
Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy.STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice.These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM.
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Gabriela
G
Rozic
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Lena
L
Paukov
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
Jana
J
Jakubikova
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Dikla
D
Ben-Shushan
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Adrian
A
Duek
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Medical Education, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.
Adi
A
Leiba
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Abraham
A
Avigdor
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Arnon
A
Nagler
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Merav
M
Leiba
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects*; D009101:Multiple Myeloma / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005663:Furans; D007211:Indoles; C000626615:STK405759; D011065:Poly(ADP-ribose) Polymerases; C505530:CASP8 protein, human; D053181:Caspase 8
AKT; apoptosis; cell cycle; multiple myeloma; tubulin