Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress.
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.
Hsiao
Che-Jen
CJ
School of Pharmacy, National Taiwan University, Taipei, Taiwan.
Ho
Yunn-Fang
YF
Hsu
John T-A
JT
Chang
Wei-Ling
WL
Chen
Yi-Cheng
YC
Shen
Ya-Ching
YC
Lyu
Ping-Chiang
PC
Guh
Jih-Hwa
JH
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*
D002243:Carbolines; C487937:Mana-Hox; D014404:Tubulin; D050257:Tubulin Modulators