(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization, induces G₂/M arrest, and triggers apoptosis in human leukemia HL-60 cells

Magalhães, Hemerson I.F.; Wilke, Diego V.; Bezerra, Daniel P.; Cavalcanti, Bruno C.; Rotta, Rodrigo; de Lima, Dênis P.; Beatriz, Adilson; Moraes, Manoel O.; Diniz-Filho, Jairo; Pessoa, Claudia

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization, induces G₂/M arrest, and triggers apoptosis in human leukemia HL-60 cells

2013

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a known cytotoxic compound belonging to the phenstatin family. However, the exact mechanism of action of PHT-induced cell death remains to be determined. The aim of this study was to investigate the mechanisms underlying PHT-induced cytotoxicity. We found that PHT displayed potent cytotoxicity in different tumor cell lines, showing IC₅₀ values in the nanomolar range. Cell cycle arrest in G₂/M phase along with the augmented metaphase cells was found. Cells treated with PHT also showed typical hallmarks of apoptosis such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of the caspase 3/7 and 8 activation, loss of mitochondrial membrane potential, and internucleosomal DNA fragmentation without affecting membrane integrity. Studies conducted with isolated tubulin and docking models confirmed that PHT binds to the colchicine site and interferes in the polymerization of microtubules. These results demonstrated that PHT inhibits tubulin polymerization, arrests cancer cells in G₂/M phase of the cell cycle, and induces their apoptosis, exhibiting promising anticancer therapeutic potential.

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