title: (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization, induces G2/M arrest, and triggers apoptosis in human leukemia HL-60 cells.
abstract: (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.
authors.affiliation: Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil; Centro de Ciências da Saúde, Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil.
authors.forename: Hemerson I F
authors.initials: HI
authors.lastname: Magalhães
authors.forename: Diego V
authors.initials: DV
authors.lastname: Wilke
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bezerra
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Cavalcanti
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Rotta
authors.forename: Dênis P
authors.initials: DP
authors.lastname: de Lima
authors.forename: Adilson
authors.initials: A
authors.lastname: Beatriz
authors.forename: Manoel O
authors.initials: MO
authors.lastname: Moraes
authors.forename: Jairo
authors.initials: J
authors.lastname: Diniz-Filho
authors.forename: Claudia
authors.initials: C
authors.lastname: Pessoa
mesh_terms: D017302:Annexins / Q000378:metabolism; D000963:Antimetabolites; D017209:Apoptosis / Q000187:drug effects*; D001577:Benzophenones / Q000138:chemical synthesis / Q000494:pharmacology*; D001973:Bromodeoxyuridine; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D020552:Comet Assay; D053938:DNA Fragmentation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008958:Models, Molecular; D058105:Polymerization; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin / Q000096:biosynthesis*; D050257:Tubulin Modulators
chemical_list: C560639:(4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone; D017302:Annexins; D000963:Antimetabolites; D001577:Benzophenones; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; D020169:Caspases; C022616:thiazolyl blue; D001973:Bromodeoxyuridine
keywords: (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone; 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; 5-bromo-20-deoxyuridine; Apoptosis; BrdU; CA-4; CA-4P; Caspase activation; DI; MTT; PHT; Phenstatins; ROS; TNF-α; Tubulin inhibitors; combretastatin A-4; combretastatin-A4-phosphate; damage index; reactive oxygen species; tumor necrosis factor-α