A novel bisindole-PBD conjugate causes DNA damage induced apoptosis via inhibition of DNA repair pathway

Abstract

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. DNA repair pathways protect the cells from tumor progression caused as a result of DNA damage induced by irradiation or due to chemotherapeutic treatment. Many promising anticancer agents have been identified that target specific DNA repair pathways in response to DNA damage thereby leading to apoptosis. Here we identified a novel bisindole-PBD conjugate that possess potent anticancer activity in breast cancer cells. Further studies aimed at understanding the mechanism of action of the molecule showed its role in DNA damage induced apoptosis via inhibition of DNA repair pathway. Trypan blue and BrdU assay exhibited a dose-dependent 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 downregulation of Bcl-XL and activation of Bax showed DNA damage induced apoptosis in MCF-7 and MDAMB-231 cells. 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.

Keywords: :

• DNA damage
• ATR
• ROS
• apoptosis
• DNA repair

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors acknowledge CSIR 12th FYP (CSC0111) for the financial support. P.S. thanks CSIR for providing the SRF (ID 8169). Special thanks go to CCMB Cell Culture Facility and Y. Suresh for conducting all the flow cytometry experiments and P. Devender for maintaining the mammalian cell culture.