Oncotarget

Research Papers:

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 and Merav Leiba _

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Oncotarget. 2016; 7:62572-62584. https://doi.org/10.18632/oncotarget.11539

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Abstract

Gabriela Rozic1, Lena Paukov1, Jana Jakubikova3, Dikla Ben-Shushan1, Adrian Duek1, Adi Leiba2,4, Abraham Avigdor1,2, Arnon Nagler1,2, Merav Leiba1,2

1Division of Hematology and BMT, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

3Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA

4Department of Medical Education, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA

Correspondence to:

Merav Leiba, email: [email protected]

Keywords: multiple myeloma, cell cycle, apoptosis, tubulin, AKT

Received: March 01, 2016     Accepted: August 09, 2016     Published: August 23, 2016

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.


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