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

Gabriela Rozic, Lena Paukov, Jana Jakubikova, Dikla Ben-Shushan, Adrian Duek, Adi Leiba, Abraham Avigdor, Arnon Nagler, Merav Leiba

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 drugefflux 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.

Original languageEnglish
Pages (from-to)62572-62584
Number of pages13
JournalOncotarget
Volume7
Issue number38
DOIs
StatePublished - 1 Jan 2016
Externally publishedYes

Keywords

  • AKT
  • Apoptosis
  • Cell cycle
  • Multiple myeloma
  • Tubulin

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