Synthetic Diphenylacetylene-Based Retinoids Induce DNA Damage in Chinese Hamster Ovary Cells without Altering Viability

Abstract

All-trans-retinoic acid (ATRA), the active metabolite of vitamin A, plays a pivotal role in cell differentiation, proliferation and embryonic development. It is an effective therapy for dermatological disorders and malignancies. ATRA is prone to isomerization and oxidation, which can affect its activity and selectivity. Novel diphenylacetylene-based ATRA analogues with increased stability can help to overcome these problems and may offer significant potential as therapeutics for a variety of cancers and neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we investigated the effects of these retinoids on cell viability and genotoxicity in the widely used model system of the rapidly proliferating Chinese hamster ovary cell line. DC360 is a fluorescent ATRA analogue and DC324 is a non-active derivative of DC360. EC23, DC525, DC540, DC645, and DC712 are promising analogues with increased bioactivity. The cytotoxic activity of the compounds was evaluated by ATP assay and DNA damage was tested by comet assay. No cytotoxicity was observed in the 10−6–10−5 M concentration range. All compounds induced DNA migration similar to ATRA, but DC324, DC360 and EC23 did so to a greater extent, particularly at higher concentrations. We believe that retinoid receptor-independent genotoxicity is a general characteristic of these compounds; however, further studies are needed to identify the molecular mechanisms and understand their complex biological functions.

Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach

“…Usually, ATRA and other vitamin A supplements do not induce structural modifications in chromosomes of human embryonic mesenchymal cells during differentiation stages [ 104 ]. However, some synthetic retinoids have been shown to induce their anti-cancer activity through the induction of DNA double breaks (DDBs), genotoxicity and chromosomal aberrations that remain unrepaired in the next cell generations inducing cellular apoptosis and necrosis [ 105 ]. This observation was matched with our data obtained using the sensitive method for the determination of DNA damage by diphenylamine assay, which is characterized as a simple method for the manipulation of any type of cell lines where the resulting colorimetric data is easily quantitated and highly reproducible [ 106 ].…”

A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects

“…Diphenylacetylene-based all- trans retinoic acid (ATRA) analogues with enhanced stability may hold tremendous promise as therapies for large number of cancers and neurological conditions. 80 In addition, diphenylacetylene derivatives acted as antimicrobial peptide mimetics. 81…”

“…Diphenylacetylene-based all-trans retinoic acid (ATRA) analogues with enhanced stability may hold tremendous promise as therapies for large number of cancers and neurological conditions. 80 In addition, diphenylacetylene derivatives acted as antimicrobial peptide mimetics. 81 Over the past decade, olenic polymerization which catalyzed by transition metals has great prominence in both academic and industrial research.…”