Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress
Journal
Naunyn-Schmiedeberg's Archives of Pharmacology
Journal Volume
378
Journal Issue
6
Pages
599-608
Date Issued
2008
Author(s)
Abstract
Tubulin and deoxyribonucleic acid (DNA) are two potential targets for the development of cancer chemotherapeutic agents. Mana-Hox is a synthetic derivative of β-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. ? 2008 Springer-Verlag.
Subjects
DNA damage; Mitochondria-mediated apoptosis; Mitotic arrest; Tubulin binding
SDGs
Other Subjects
antineoplastic agent; ATM protein; aurora A kinase; beta carboline derivative; caspase 3; cell cycle protein; cyclin A; cyclin dependent kinase 2; cyclin E; glycoprotein P; histone deacetylase; mana hox; protein bcl 2; protein mcl 1; protein MPM 2; protein p53; serine; unclassified drug; antineoplastic activity; apoptosis; article; cancer cell culture; cell cycle arrest; cell proliferation; controlled study; DNA damage; double stranded DNA break; down regulation; drug potency; enzyme activation; enzyme inhibition; human; human cell; immunofluorescence; male; microtubule assembly; mitochondrion; mitosis inhibition; prostate cancer; protein phosphorylation; turbidity; Apoptosis; Carbolines; Cell Line, Tumor; Cell Proliferation; DNA Damage; Humans; Male; Mitosis; Phosphorylation; Prostatic Neoplasms; Tubulin; Tubulin Modulators
Type
journal article