G-quadruplex stabilizer 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide induces accelerated senescence and inhibits tumorigenic properties in cancer cells.
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 degrees C and has a potent inhibitory effect on telomerase activity. Treatment of H1299 cancer cells with 0.5 mumol/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 beta-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 BMVC were 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.
Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei 11221, Taiwan, Republic of China.
Fong-Chun
FC
Huang
Cheng-Chung
CC
Chang
Pei-Jen
PJ
Lou
I-Chun
IC
Kuo
Chih-Wei
CW
Chien
Chin-Tin
CT
Chen
Fu-Ying
FY
Shieh
Ta-Chau
TC
Chang
Jing-Jer
JJ
Lin
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000737:chemistry / Q000187:drug effects*
C486012:3,6-bis(1-methyl-4-vinylpyridium)carbazole diiodide; D000970:Antineoplastic Agents; D002227:Carbazoles; D011726:Pyridinium Compounds; D004247:DNA; D019098:Telomerase