Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression.
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 p21(Waf/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 p21(Waf1/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.
Centre for Obesity Research and Education (CORE), Robert Gordon University, Sir Ian Wood Building, Garthdee Road, Aberdeen, Scotland, AB10 7GJ, United Kingdom. Electronic address: g.barron@rgu.ac.uk.
Gemma A
GA
Barron
School of Pharmacy and Life Sciences (PALS), Robert Gordon University, Sir Ian Wood Building, Garthdee Road, Aberdeen, Scotland, AB10 7GJ, United Kingdom. Electronic address: m.goua@rgu.ac.uk.
Marie
M
Goua
Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan. Electronic address: kuraoka@chem.es.osaka-u.ac.jp.
Isao
I
Kuraoka
Centre for Obesity Research and Education (CORE), Robert Gordon University, Sir Ian Wood Building, Garthdee Road, Aberdeen, Scotland, AB10 7GJ, United Kingdom. Electronic address: g.bermano@rgu.ac.uk.
Giovanna
G
Bermano
Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan. Electronic address: iwai@chem.es.osaka-u.ac.jp.
Shigenori
S
Iwai
Centre for Obesity Research and Education (CORE), Robert Gordon University, Sir Ian Wood Building, Garthdee Road, Aberdeen, Scotland, AB10 7GJ, United Kingdom; School of Pharmacy and Life Sciences (PALS), Robert Gordon University, Sir Ian Wood Building, Garthdee Road, Aberdeen, Scotland, AB10 7GJ, United Kingdom. Electronic address: p.v.s.kong-thoo-lin@rgu.ac.uk.
Paul
P
Kong Thoo Lin
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D003514:Cyclohexylamines / Q000494:pharmacology*; D053960:DNA Breaks / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D053644:Naphthalimides / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003514:Cyclohexylamines; D053644:Naphthalimides; C000607203:bisnaphthalimidopropyl diaminodicyclohexylmethane
Bisnaphthalimidopropyl; DNA damage; DNA repair; Triple negative breast cancer; p21 expression