title: Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress.
abstract: Tubulin and deoxyribonucleic acid (DNA) are two potential targets for the development of cancer chemotherapeutic agents. Mana-Hox is a synthetic derivative of beta-carboline, a structure relevant to marine sponge component, manzamine. In this study, Mana-Hox induced an inhibition of cell proliferation in several types of human cancer cell lines, including androgen-independent prostate cancer PC-3 and DU-145, hepatocellular carcinoma Hep3B and HepG2, and colorectal cancer HT-29 cells. The p53-null PC-3 cells were used for to anticancer mechanisms. Mana-Hox stimulated an increase of ataxia telangiectasia mutated (ATM) phosphorylation on Ser-1981, indicating the induction of DNA double-strand breaks. It also displayed an inhibitory effect on tubulin polymerization using tubulin turbidity assay and immunofluorescence identification. However, it only showed a minor inhibition on the activity of Aurora kinase and histone deacetylase. Mana-Hox induced mitotic arrest of the cell cycle identified by downregulation of cyclin E, cyclin A, and cyclin-dependent kinase 2 (Cdk2) and an increase of MPM-2 expression. Next, it caused Bcl-2 phosphorylation on Ser-70, downregulation of Mcl-1 expression, and activation of caspase-3, leading to apoptotic cell death. Notably, Mana-Hox was not a P-glycoprotein (P-gp) substrate and showed equipotent activity against P-gp-rich cancer cells. We conclude that Mana-Hox induces dual effects on DNA damage and tubulin depolymerization, leading to mitotic arrest and activation of mitochondria-mediated apoptotic pathways. Data provide evidence that the anticancer strategy of dual-action targets could be a potential anticancer approach.
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors.forename: Che-Jen
authors.initials: CJ
authors.lastname: Hsiao
authors.forename: Yunn-Fang
authors.initials: YF
authors.lastname: Ho
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Chang
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Shen
authors.forename: Ping-Chiang
authors.initials: PC
authors.lastname: Lyu
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004249:DNA Damage; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D002243:Carbolines; C487937:Mana-Hox; D014404:Tubulin; D050257:Tubulin Modulators