title: Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of beta-tubulin at Cys 12 and suppression of microtubule dynamics.
abstract: 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 micromol/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 modified beta-tubulin at residue Cys12, forming beta-tubulin-SS-fluorobenzyl. The binding site differs from known antimicrotubule agents, suggesting that BFBTS functions as a novel antimicrotubule agent. BFBTS at a dose of 25 mg/kg inhibited tumor growth with relative tumor growth rates of 19.91%, 18.5%, and 23.42% in A549 lung cancer, Bcap-37 breast cancer, and SKOV3 ovarian cancer xenografts, respectively. Notably, BFBTS was more potent against MDR1-overexpressing MCF7/adr breast cancer xenografts with a relative tumor growth rate of 12.3% than paclitaxel with a rate of 43.0%. BFBTS displays a novel antimicrotubule agent with potentials for cancer therapeutics.
authors.affiliation: Hangzhou High Throughput Drug Screening Center, ACEA Biosciences, Inc., 6779 Mesa Ridge Road, Suite 100, San Diego, CA 92121, USA.
authors.forename: Wanhong
authors.initials: W
authors.lastname: Xu
authors.forename: Biao
authors.initials: B
authors.lastname: Xi
authors.forename: Jieying
authors.initials: J
authors.lastname: Wu
authors.forename: Haoyun
authors.initials: H
authors.lastname: An
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhu
authors.forename: Yama
authors.initials: Y
authors.lastname: Abassi
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.forename: Michelle
authors.initials: M
authors.lastname: Gaylord
authors.forename: Baoqin
authors.initials: B
authors.lastname: Geng
authors.forename: Huifang
authors.initials: H
authors.lastname: Yan
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
authors.forename: Meihua
authors.initials: M
authors.lastname: Sui
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005464:Fluorobenzenes / Q000737:chemistry / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004220:Disulfides; D005464:Fluorobenzenes; D013440:Sulfides; D014404:Tubulin; C528265:fluorapacin; D003545:Cysteine