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Oncotarget. 2016 Sep 20;7(38):62572-62584. doi: 10.18632/oncotarget.11539.

The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo.

Author information

1
Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
2
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
4
Department of Medical Education, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.

Abstract

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.

KEYWORDS:

AKT; apoptosis; cell cycle; multiple myeloma; tubulin

PMID:
27613836
PMCID:
PMC5308747
DOI:
10.18632/oncotarget.11539
[Indexed for MEDLINE]
Free PMC Article

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