A novel synthetic 1,3-phenyl bis-thiourea compound targets microtubule polymerization to cause cancer cell death

Jennifer C. Shing, Jae Won Choi, Robert Chapman, Mark A. Schroeder, Jann N. Sarkaria, Abdul Fauq, Richard J. Bram

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Microtubules are essential cytoskeletal components with a central role in mitosis and have been particularly useful as a cancer chemotherapy target. We synthesized a small molecule derivative of a symmetrical 1,3-phenyl bis-thiourea, (1,1'-[1,3-phenylene]bis[3-(3,5-dimethylphenyl)thiourea], named "41J"), and identified a potent effect of the compound on cancer cell survival. 41J is cytotoxic to multiple cancer cell lines at nanomolar concentrations. Cell death occurred by apoptosis and was preceded by mitotic arrest in prometaphase. Prometaphase arrest induced by 41J treatment was accompanied by dissociation of cyclin B1 levels from the apparent mitotic stage and by major spindle abnormalities. Polymerization of purified tubulin in vitro was directly inhibited by 41J, suggesting that the compound works by directly interfering with microtubule function. Compound 41J arrested the growth of glioblastoma multiforme xenografts in nude mice at doses that were well-tolerated, demonstrating a relatively specific antitumor effect. Importantly, 41J overcame drug resistance due to β-tubulin mutation and P-glycoprotein overexpression. Compound 41J may serve as a useful new lead compound for anticancer therapy development.

Original languageEnglish (US)
Pages (from-to)895-905
Number of pages11
JournalCancer Biology and Therapy
Volume15
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Chemotherapy
  • Drug resistance
  • Microtubule
  • Mitosis
  • Xenograft

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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