Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics

Bis(4-fluorobenzyl)trisulfide (BFBTS) is a synthetic molecule derived from a bioactive natural product, dibenzyltrisulfide, found in a subtropical shrub, Petiveria allieacea. BFBTS has potent anticancer activities to a broad spectrum of tumor cell lines with IC50 values from high nanomolar to low micromolar and showed equal anticancer potency between tumor cell lines overexpressing multidrug-resistant gene, MDR1 (MCF7/adr line and KBv200 line), and their parental MCF7 line and KB lines. BFBTS inhibited microtubule polymerization dynamics in MCF7 cells, at a low nanomolar concentration of 54 nmol/L, while disrupting microtubule filaments in cells at low micromolar concentration of 1 μmol/L. Tumor cells treated with BFBTS were arrested at G2-M phase, conceivably resulting from BFBTS-mediated antimicrotubule activities. Mass spectrometry studies revealed that BFBTS bound and eceived 6/22/09; revised 10/23/09; accepted 10/25/09; published nlineFirst 12/8/09. rant Support: Hangzhou Municipal Grant for new drug discovery and evelopment and Zhejiang Technology and Science Department Grant for ew drug discovery and development. he costs of publication of this article were defrayed in part by the ayment of page charges. This article must therefore be hereby marked dvertisement in accordance with 18 U.S.C. Section 1734 solely to dicate this fact. ote: Supplementary material for this article is available at Molecular ancer Therapeutics Online (http://mct.aacrjournals.org/). . Xu and B. Xi contributed equally to this work. equests for reprints: Xiao Xu, ACEA Biosciences, Inc., 6779 Mesa Ridge oad, Suite 100, San Diego, CA 92121. Phone: 858-724-0928, ext. 006; Fax: 858-724-0927. E-mail: [email protected] opyright © 2009 American Association for Cancer Research. oi:10.1158/1535-7163.MCT-09-0548 R O