Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt.
Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, Cairo 11795, Egypt.
Int J Mol Sci. 2022 Aug 21;23(16):9442. doi: 10.3390/ijms23169442.
Colorectal cancer therapies have produced promising clinical responses, but tumor cells rapidly develop resistance to these drugs. It has been previously shown that EC19 and EC23, two EC-synthetic retinoids, have single-agent preclinical anticancer activity in colorectal carcinoma. Here, isobologram analysis revealed that they have synergistic cytotoxicity with retinoic acid receptor (RAR) isoform-selective agonistic retinoids such as AC261066 (RARβ2-selective agonist) and CD437 (RARγ-selective agonist) in Caco-2 cells. This synergism was confirmed by calculating the combination index (lower than 1) and the dose reduction index (higher than 1). Flow cytometry of combinatorial IC (the concentration causing 50% cell death) confirmed the cell cycle arrest at the SubG-G phase with potentiated apoptotic and necrotic effects. The reported synergistic anticancer activity can be attributed to their ability to reduce the expression of ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp1), breast cancer resistance protein (BCRP) and multi-drug resistance-associated protein-1 (MRP1) and Heat Shock Protein 70 (Hsp70). This adds up to the apoptosis-promoting activity of EC19 and EC23, as shown by the increased Caspase-3/7 activities and DNA fragmentation leading to DNA double-strand breaks. This study sheds the light on the possible use of EC-synthetic retinoids in the rescue of multi-drug resistance in colorectal cancer using Caco-2 as a model and suggests new promising combinations between different synthetic retinoids. The current in vitro results pave the way for future studies on these compounds as possible cures for colorectal carcinoma.
结直肠癌的治疗方法已经产生了有前景的临床反应，但肿瘤细胞很快对这些药物产生了耐药性。此前已经表明，EC19 和 EC23 这两种 EC 合成视黄醇，在结直肠癌细胞中有单一药物的临床前抗癌活性。在这里，等效应线分析显示，它们与维甲酸受体（RAR）同工型选择性激动剂视黄醇，如 AC261066（RARβ2 选择性激动剂）和 CD437（RARγ 选择性激动剂）在 Caco-2 细胞中具有协同细胞毒性。这种协同作用通过计算组合指数（低于 1）和剂量减少指数（高于 1）得到了证实。组合 IC 的流式细胞术（导致 50%细胞死亡的浓度）证实了细胞周期在 SubG-G 期停滞，并增强了凋亡和坏死作用。报道的协同抗癌活性可归因于它们降低 ATP 结合盒（ABC）转运蛋白表达的能力，包括 P-糖蛋白（P-gp1）、乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白 1（MRP1）和热休克蛋白 70（Hsp70）。这增加了 EC19 和 EC23 的促凋亡活性，如增加的 Caspase-3/7 活性和导致 DNA 双链断裂的 DNA 片段化所表明的那样。这项研究揭示了 EC 合成视黄醇在结直肠癌中挽救多药耐药的可能用途，Caco-2 作为模型，并提出了不同合成视黄醇之间新的有前途的组合。目前的体外结果为这些化合物作为结直肠癌潜在治疗方法的进一步研究铺平了道路。
