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.
Highlights
Microtubules are dynamic polymers of α-tubulin and β-tubulin heterodimers, arranged in the form of slender filaments whose polymerization dynamics are tightly regulated both spatially and temporally
The IC50 values derived from normalized cell index (CI) at 48 hours after BFBTS treatment in 10 tumor cell lines are listed in Table 1, and ranged from high nanomolar concentration (∼400 nmol/L for Bcap-37 line) to high micromolar concentration (∼113 μmol/L for MNK line)
We found that the sulfhydryl group of Cys12 of βtubulin was covalently modified and formed a disulfide bridge with BFBTS, resulting in β-tubulin-SS-fluorobenzyl
Summary
Microtubules are dynamic polymers of α-tubulin and β-tubulin heterodimers, arranged in the form of slender filaments whose polymerization dynamics are tightly regulated both spatially and temporally. Microtubules exchange their tubulin with soluble tubulin in the cytoplasmic pool with half times of ∼3 minutes to several hours [2, 3]. Mitotic spindle microtubules with a short tubulin half-life of ∼15 seconds are 20 to 50 times more dynamic than interphase microtubule [3,4,5]. Diversified group of microtubuletargeted drugs can alter microtubule polymerization and dynamics in a wide variety of ways [1] and are classified based on their distinct tubulin-binding domains, including Vinca domain, colchicine domain, taxane domain, and other domains distinct from the above three domains [1, 7]
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