Investigating the anti-cancer potential of carbazole derivative BMVC

• Main Authors: Fong-Chun Huang, 黃豐淳
• Other Authors: Jing-Jer Lin
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/76531467381383042977

碩士 === 國立陽明大學 === 生物藥學研究所 === 94 === Telomeres consist of tandem repeats of guanine-rich sequences that can fold into a variety of four-stranded structures, quadruplexes. The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Inhibition of telomere maintenance can be achieved by stabilization of a quadruplex structure for the telomere end. Previously, we have identified a G-quadruplex-interactive compound, 3,6-bis (1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), which inhibited telomerase at sub-micro molar range. Here we assessed the effects of BMVC on H1299 human non-small cell lung cancer. Treatment of cancer cells with BMVC did not cause acute toxicity, however, the BMVC-treated cells ceased to divide after a lag period. Hallmarks of senescence including morphological changes, the senescence associated ��-galactosidase activity, and decreased BrdU incorporation were detected in BMVC-treated cancer cells. The BMVC-induced senescence phenotype is accompanied by a progressive telomere shortening and detection of the DNA damage foci, suggesting that BMVC caused telomere uncapping after long-term treatment. Interestingly, unlike other telomerase inhibitors, the BMVC-treated cancer cells showed a fast telomere shortening rate and short lag period of growth before entering senescence. Accelerated senescence of BMVC-treated cancer cells further suppressed the tumor-related properties of cancer cells including cell migration, colony-forming ability, and anchorage-independent growth. Consistent with the observations from cellular experiments, the tumorigenic potential of cancer cells was also reduced in mouse xenografts after BMVC treatments. Together, our results indicated that BMVC is a potent G-quadruplex stabilizer and telomerase inhibitor that limited the growth of tumor cells both in vitro and in vivo.