Studies on the mechanism of action of Bisindole PBD in breast cancer cell proliferation

Abstract

The objective of this doctoral thesis specifically focused on understanding and deciphering the mechanistic role of a small molecule bisindole-PBD in breast cancer cell proliferation. The rationale behind choosing the topic was to put a new insight on breast cancer therapeutics where two active pharmacophores (bisindole and PBD) of bisindole-PBD (5b) enhanced the anti cancer property without showing newlinetoxicity in normal epithelial breast cells. In the first phase of the study newlineanti angiogenesis role of bisindole-PBD in breast cancer cells had been explored. The findings highlighted the potent therapeutic role of 5b in inhibiting tumor angiogenesis in vitro and in vivo inhibition in CAM assay. In another attempt, we showed the role of bisindole-PBD in DNA damage induced apoptosis and possible role in inhibition of DNA repair newlinepathway. DNA damage response (DDR) that includes cell cycle check points, DNA repair, apoptosis and senescence is intimately linked with cancer. It shields an organism against cancer development when genomic integrity fails. Further studies aimed at understanding the mechanism of action of bisindole-PBD on DNA damage induced apoptosis via inhibition of DNA repair pathway. Trypan blue and BrdU assay exhibited a dose newlinedependent effect. Single stranded DNA damage was observed by COMET assay. In addition DNA damage induced ROS generation with simultaneous activation of ATM and ATR upon compound treatment was observed. Further down regulation of Bcl-XL and activation of Bax showed DNA damage induced apoptosis in MCF-7 and MDAMB-231 newlinecells. In conclusion, it can be summarized that bisindole-PBD conjugate induces DNA damage in a dose dependent (2, 4 and 8 µM) manner by inhibiting the DNA repair genes. newline