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Abstract
English Abstract
All-trans retinoic acid (ATRA) is a biologically active vitamin-A derivative that induces differentiation and inhibits cellular proliferation and migration of many cancer cells. However,there is urgent need to develop new synthetic derivatives of ATRA due to the rapid emergence of resistance. In addition, the doses of ATRA used in clinical settings are often high due to environmental instability and isomerization leading to additional adverse toxic effects. In the present study, EC19 and EC23, two synthetic retinoids with known differential effect on stem cell differentiation, have been screened for their in-vitroantiproliferative and cytotoxic activity using an array of different cancer cell lines. MTT assay revealed that HepG2, Caco-2, and MCF-7 are the most sensitive cell lines with IC50 values; HepG2 (ATRA; 36.2, EC19; 42.2 and EC23; 0.74 µM), Caco-2 (ATRA; 58.0, EC19; 10.8 and EC23; 14.7 µM) and MCF-7 (ATRA; 99.0, EC19; 9.4 and EC23; 5.56 µM). Caco-2 cell line was selected for further biochemical investigations scrutinizing mechanism. All retinoids induced early stage of apoptosis with EC19 had the highest potency compared to ATRA and EC23 with cell cycle arrest at subG0-G1, -S and G2/M phases. In addition, EC19 markedly reduced cellular invasion through semipermeable membrane of Transwell Boyden chamber due to overexpression of E-cadherin, RAI2 and WRN genes and downregulation of NF-κB. EC19 was also able to significantly reduce both intracellular glutamate and antioxidant power of Caco-2 cells leading to reduced proliferation and increased susceptibility to oxidative stress. Overall, the present study suggests that EC-synthetic retinoids, particularly EC19, can be effective, alone or in combinations, for the treatment of colorectal cancer. Interestingly, isobologram analysis revealed the combined synergistic effects with 5-fluorouracil with significant reduction in IC50. In Caco-2 cells,furtherin-vivo animal studies are recommended to prove the efficiency of the tested retinoids and hopefully pave the way for subsequent multi-centre clinical trials.