A G-quadruplex Stabilizer Induces M-phase Cell Cycle Arrest. Export

@article{citeulike:4896831, abstract = {G-quadruplex stabilizers such as telomestatin and HXDV bind with exquisite specificity to G-quadruplexes, but not to triplex, duplex, or single-stranded DNAs. Studies have suggested that the antiproliferative and possibly anti-tumor activities of these compounds are linked to their inhibitory effect on telomerase and/or telomere function. In the current studies, we show that HXDV, a synthetic analog of telomestatin, exhibits antiproliferative activity against both telomerase-positive and -negative cells and induces robust apoptosis within 16 h of treatment, suggesting a mode of action independent of telomerase. HXDV was also shown to inhibit cell cycle progression causing M-phase cell cycle arrest, as evidenced by accumulation of cells with 4 n DNA content, increased mitotic index, separated centrosomes, elevated histone H3 phosphorylation at Ser-10 (an M-phase marker), and defective chromosome alignment and spindle fiber assembly (revealed by time-lapse microscopy). The M-phase arrest caused by HXDV paralleled with reduction in the expression level of the major M-phase checkpoint regulator Aurora A. All these cellular effects appear to depend on the G-quadruplex binding activity of HXDV as its non-G-quadruplex binding analog, TXTLeu, is completely devoid of all these effects. In the aggregate, our results suggest that HXDV, which exhibits anti-proliferative and apoptotic activities, is also a novel M-phase blocker, with a mode of action dependent on its G-quadruplex binding activity.}, author = {Tsai, Yuan-Chin C. and Qi, Haiyan and Lin, Chao-Po P. and Lin, Ren-Kuo K. and Kerrigan, John E. and Rzuczek, Suzanne G. and Lavoie, Edmond J. and Rice, Joseph E. and Pilch, Daniel S. and Lyu, Yi Lisa L. and Liu, Leroy F.}, citeulike-article-id = {4896831}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M109.020230}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19531483}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19531483}, day = {21}, doi = {10.1074/jbc.M109.020230}, issn = {0021-9258}, journal = {The Journal of biological chemistry}, keywords = {3c, c-myc, cell-cycle, g-quadruplex, telomere, topoisomerase}, month = {August}, number = {34}, pages = {22535--22543}, posted-at = {2009-09-09 05:08:05}, priority = {2}, title = {A G-quadruplex Stabilizer Induces M-phase Cell Cycle Arrest.}, url = {http://dx.doi.org/10.1074/jbc.M109.020230}, volume = {284}, year = {2009} }

TY - JOUR ID - citeulike:4896831 L3 - citeulike-article-id:4896831 N2 - G-quadruplex stabilizers such as telomestatin and HXDV bind with exquisite specificity to G-quadruplexes, but not to triplex, duplex, or single-stranded DNAs. Studies have suggested that the antiproliferative and possibly anti-tumor activities of these compounds are linked to their inhibitory effect on telomerase and/or telomere function. In the current studies, we show that HXDV, a synthetic analog of telomestatin, exhibits antiproliferative activity against both telomerase-positive and -negative cells and induces robust apoptosis within 16 h of treatment, suggesting a mode of action independent of telomerase. HXDV was also shown to inhibit cell cycle progression causing M-phase cell cycle arrest, as evidenced by accumulation of cells with 4 n DNA content, increased mitotic index, separated centrosomes, elevated histone H3 phosphorylation at Ser-10 (an M-phase marker), and defective chromosome alignment and spindle fiber assembly (revealed by time-lapse microscopy). The M-phase arrest caused by HXDV paralleled with reduction in the expression level of the major M-phase checkpoint regulator Aurora A. All these cellular effects appear to depend on the G-quadruplex binding activity of HXDV as its non-G-quadruplex binding analog, TXTLeu, is completely devoid of all these effects. In the aggregate, our results suggest that HXDV, which exhibits anti-proliferative and apoptotic activities, is also a novel M-phase blocker, with a mode of action dependent on its G-quadruplex binding activity. IS - 34 JF - The Journal of biological chemistry SN - 0021-9258 EP - 22543 TI - A G-quadruplex Stabilizer Induces M-phase Cell Cycle Arrest. VL - 284 SP - 22535 KW - 3c KW - c-myc KW - cell-cycle KW - g-quadruplex KW - telomere KW - topoisomerase AU - Tsai, Yuan-Chin AU - Qi, Haiyan AU - Lin, Chao-Po AU - Lin, Ren-Kuo AU - Kerrigan, John AU - Rzuczek, Suzanne AU - Lavoie, Edmond AU - Rice, Joseph AU - Pilch, Daniel AU - Lyu, Yi Lisa AU - Liu, Leroy PY - 2009/08/21/ UR - http://dx.doi.org/10.1074/jbc.M109.020230 ER -