4.7 Article

I-CBP112 declines overexpression of ATP-binding cassette transporters and sensitized drug-resistant MDA-MB-231 and A549 cell lines to chemotherapy drugs

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BIOMEDICINE & PHARMACOTHERAPY
卷 168, 期 -, 页码 -

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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2023.115798

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CREB-binding protein/Histone; acetyltransferase p300 (CBP/EP300); bromodomain inhibitor; Multi-drug resistance (MDR); ATP-binding cassette transporters (ABC); Triple-negative breast cancer; Non-small cell lung cancer

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This study tested the efficacy of I-CBP112, a CBP/EP300 bromodomain inhibitor, in overcoming drug resistance in breast cancer and lung cancer models. It was found that I-CBP112 significantly reduced the overexpression of ATP-binding cassette transporters, thereby increasing intracellular drug accumulation and cytotoxicity. The study also demonstrated that I-CBP112 polarized human macrophages into proinflammatory phenotypes. Importantly, I-CBP112 did not show toxicity to primary cell lines or enhance drug toxicity to blood-immune cells.
Despite extensive efforts and ongoing progress in personalized anticancer approaches, chemotherapy remains the first line or the only treatment for some tumors that may develop resistance to chemotherapeutics in time due to inter alia overexpression of ATP-binding cassette transporters. Using clinically-relevant resistant models of triple negative breast cancer (MDA-MB-231; TNBC) as well as non-small cell lung cancer (A549; NSCLC), we tested the efficacy of I-CBP112 - CBP/EP300 bromodomain inhibitor to overcome drug resistance by declining ABC gene transcription. I-CBP112 significantly reduced ABCB1, ABCC1, ABCC2, ABCC3, ABCC5 and ABCG2 in all resistant lines, as well as ABCC10 in TNBC and ABCC4 in paclitaxel-resistant NSCLC, thereby increasing intracellular drug accumulation and cytotoxicity in 2D and 3D cultures. This was phenocopied only by the joint effect of ABC inhibitors such as tariquidar (ABCB1 - P-glycoprotein and ABCG2) and MK-571 (ABCC), whereas single inhibition of ABCB1/ABCG2 or ABCC proteins did not affect drug accumulation, thereby implying the need of simultaneous deficiency in activity of majority of drug pumps for enhanced drug retention. I-CBP112 failed to directly inhibit activity of ABCB1, ABCG2 and ABCC subfamily members at the same time. Importantly, I-CBP112 treated cancer cells polarized human macrophages into proinflammatory phenotypes. Moreover, I-CBP112 remained non-toxic to primary cell lines, nor did it enhance anticancer drug toxicity to blood-immune cells. In

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