Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression.

Barron, Gemma A.; Goua, Marie; Kuraoka, Isao; Bermano, Giovanna; Iwai, Shigenori; Kong Thoo Lin, Paul

Abstract

Bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM) bisintercalates to DNA and is a potential anti-cancer therapeutic. In an attempt to elucidate the mechanism(s) underlying the potential of BNIPDaCHM; earlier work was extended to investigate its effect on DNA damage and repair as well as cell cycle modulation, in a triple negative breast cancer (TNBC) cell line in vitro. BNIPDaCHM significantly decreased cell viability in a concentration (≥5 μM) and time (≥24 h) dependent manner. The mechanism of this growth inhibition involved alterations to cell cycle progression, an increase in the sub-G1 population and changes to plasma membrane integrity/permeability observed by flow cytometry and fluorescence microscopy with acridine orange/ethidium bromide staining. Using single cell gel electrophoresis (Comet assay) and fluorescence microscopy to detect γ-H2AX-foci expression; it was found that after 4 h, ≥ 0.1 μM BNIPDaCHM treatment-induced significant DNA double strand breaks (DSBs). Moreover, exposure to a non-genotoxic concentration of BNIPDaCHM induced a significant decrease in the repair of oxidative DNA strand breaks induced by hydrogen peroxide. Also, BNIPDaCHM-treatment induced a significant time dependent increase in p21Waf/Cip1 mRNA expression but, did not alter p53 mRNA expression. In conclusion, BNIPDaCHM treatment in MDA-MB-231 cells was associated with a significant induction of DNA DSBs and inhibition of DNA repair at non-genotoxic concentrations via p53-independent expression of p21Waf1/Cip1. The latter may be a consequence of novel interactions between BNIPDaCHM and MDA-MB-231 cells which adds to the spectrum of therapeutically relevant activities that may be exploited in the future design and development of naphthalimide-based therapeutics.

Citation

BARRON, G.A., GOUA, M., KURAOKA, I., BERMANO, G., IWAI, S. and KONG THOO LIN, P. 2015. Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression. Chemico-biological interactions [online], 242, pages 307-315. Available from: https://doi.org/10.1016/j.cbi.2015.10.017

• Journal Article Type: Article
• Acceptance Date: Oct 18, 2015
• Online Publication Date: Oct 21, 2015
• Publication Date: Dec 5, 2015
• Deposit Date: Feb 29, 2016
• Publicly Available Date: Oct 22, 2016
• Journal: Chemico-biological interactions
• Print ISSN: 0009-2797
• Electronic ISSN: 1872-7786
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 242
• Pages: 307-315
• DOI: https://doi.org/10.1016/j.cbi.2015.10.017
• Keywords: Bisnaphthalimidopropyl; DNA damage; DNA repair; p21 expression; Triple negative breast cancer
• Public URL: http://hdl.handle.net/10059/1392
• Contract Date: Feb 29, 2016