G-quadruplex stabilizer 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide induces accelerated senescence and inhibits tumorigenic properties in cancer cells
Journal
Molecular Cancer Research
Journal Volume
6
Journal Issue
6
Pages
955-964
Date Issued
2008
Author(s)
Huang F.-C.
Chang C.-C.
Kuo I.-C.
Chien C.-W.
Shieh F.-Y.
Chang T.-C.
Abstract
Carbazole derivatives that stabilized G-quadruplex DNA structure formed by human telomeric sequence have been designed and synthesized. Among them, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) showed an increase in G-quadruplex melting temperature by 13°C and has a potent inhibitory effect on telomerase activity. Treatment of H1299 cancer cells with 0.5 μmol/L BMVC did not cause acute toxicity and affect DNA replication; however, the BMVC-treated cells ceased to divide after a lag period. Hallmarks of senescence, including morphologic changes, detection of senescence-associated β-galactosidase activity, and decreased bromodeoxyuridine incorporation, were detected in BMVC-treated cancer cells. The BMVC-induced senescence phenotype is accompanied by progressive telomere shortening and detection of the DNA damage foci, indicating that BMVC caused telomere uncapping after long-term treatments. Unlike other telomerase inhibitors, the BMVC-treated cancer cells showed a fast telomere shortening rate and a lag period of growth before entering senescence. Interestingly, BMVC also suppressed the tumor-related properties of cancer cells, including cell migration, colony-forming ability, and anchorage-independent growth, indicating that the cellular effects of BMVCwere not limited to telomeres. Consistent with the observations from cellular experiments, the tumorigenic potential of cancer cells was also reduced in mouse xenografts after BMVC treatments. Thus, BMVC repressed tumor progression through both telomere-dependent and telomere-independent pathways. Copyright ? 2008 American Association for Cancer Research.
SDGs
Other Subjects
3,6 bis(1 methyl 4 vinylpyridinium)carbazole diiodide; beta galactosidase; carbazole derivative; unclassified drug; 3,6 bis(1 methyl 4 vinylpyridium)carbazole diiodide; 3,6-bis(1-methyl-4-vinylpyridium)carbazole diiodide; antineoplastic agent; carbazole derivative; DNA; guanine quadruplex; pyridinium derivative; telomerase; anchorage independent growth; animal tissue; antineoplastic activity; article; cancer inhibition; cell aging; cell migration; colony formation; controlled study; DNA damage; drug structure; human; human cell; mouse; nonhuman; nude mouse; priority journal; telomere; tumor xenograft; animal; Bagg albino mouse; cell aging; cell proliferation; cell survival; chemistry; drug antagonism; drug effect; neoplasm; pathology; telomere; tumor cell line; Animals; Antineoplastic Agents; Carbazoles; Cell Aging; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA; G-Quadruplexes; Mice; Mice, Inbred BALB C; Neoplasms; Pyridinium Compounds; Telomerase; Telomere
Type
journal article