Induction of senescence in cancer cells by the G-quadruplex stabilizer, BMVC4, is independent of its telomerase inhibitory activity

Telomerase is the enzyme responsible for extending G-strand telomeric DNA and represents a promising target for treatment of neoplasia. Inhibition of telomerase can be achieved by stabilization of G-quadruplex DNA structures. Here, we characterize the cellular effects of a novel G-quadruplex stabilizing compound, 3,6-bis(4-methyl-2-vinylpyrazinium iodine) carbazole (BMVC4). Experimental approach: The cellular effects of BMVC4 were characterized in both telomerase-positive and alternative lengthening of telomeres (ALT) cancer cells. The molecular mechanism of how BMVC4 induced senescence is also addressed. Key

Telomerase is the enzyme responsible for extending G-strand telomeric DNA and represents a promising target for treatment of neoplasia. Inhibition of telomerase can be achieved by stabilization of G-quadruplex DNA structures. Here, we characterize the cellular effects of a novel G-quadruplex stabilizing compound, 3,6-bis(4-methyl-2-vinylpyrazinium iodine) carbazole (BMVC4). Experimental approach: The cellular effects of BMVC4 were characterized in both telomerase-positive and alternative lengthening of telomeres (ALT) cancer cells. The molecular mechanism of how BMVC4 induced senescence is also addressed. Key

BMVC4-treated cancer cells showed typical senescence phenotypes. BMVC4 induced senescence in both ALT and telomerase-overexpressing cells, suggesting that telomere shortening through telomerase inhibition might not be the cause for senescence. A large fraction of DNA damage foci was not localized to telomeres in BMVC4-treated cells and BMVC4 suppressed c-myc expression through stabilizing the G-quadruplex structure located at its promoter. These results indicated that the cellular targets of BMVC4 were not limited to telomeres. Further analyses showed that BMVC4 induced DNA breaks and activation of ataxia telangiectasia-mutated mediated DNA damage response pathway. Conclusions and implications: BMVC4, a G-quadruplex stabilizer, induced senescence by activation of pathways of response to DNA damage that was independent of its telomerase inhibitory activity. Thus, BMVC4 has the potential to be developed as a chemotherapeutic agent against both telomerase positive and ALT cancer cells.