尽管在个性化抗癌方法方面做出了广泛的努力并不断取得进展，但化疗仍然是某些肿瘤的一线或唯一治疗方法，这些肿瘤可能由于 ATP 结合盒转运蛋白的过度表达而及时产生对化疗药物的耐药性。使用三阴性乳腺癌（MDA-MB-231；TNBC）和非小细胞肺癌（A549；NSCLC）的临床相关耐药模型，我们测试了 I-CBP112 - CBP/EP300 溴结构域抑制剂的功效通过降低 ABC 基因转录来克服耐药性。 I-CBP112 显着降低所有耐药系中的 ABCB1、ABCC1、ABCC2、ABCC3、ABCC5 和 ABCG2，以及 TNBC 中的 ABCC10 和紫杉醇耐药 NSCLC 中的 ABCC4，从而增加 2D 和 3D 培养物中的细胞内药物积累和细胞毒性。仅通过 ABC 抑制剂（例如塔里奎达（ABCB1 - P-糖蛋白和 ABCG2）和 MK-571 (ABCC) ）的联合作用来模拟这一现象，而单独抑制 ABCB1/ABCG2 或 ABCC 蛋白不会影响药物蓄积，从而意味着需要同时缺乏大多数药物泵的活性以增强药物保留。 I-CBP112未能同时直接抑制ABCB1、ABCG2和ABCC亚家族成员的活性。重要的是，I-CBP112 处理的癌细胞将人类巨噬细胞极化为促炎表型。此外，I-CBP112 对原代细胞系仍然无毒，也不会增强抗癌药物对血液免疫细胞的毒性。 ADMET 特性的计算机模拟测定证实了 I-CBP112 所需的药代动力学特征。结果表明，CBP/p300 抑制剂是一种很有前景的耐药癌症表型化疗的辅助佐剂，能够降低 ABC 转运蛋白的表达。版权所有 © 2023 作者。由 Elsevier Masson SAS 出版。保留所有权利。

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 silico assay of ADMET properties confirmed the desired pharmacokinetic features of I-CBP112. The results suggest that the CBP/p300 inhibitor is a promising co-adjuvant to chemotherapy in drug-resistant cancer phenotypes, capable of decreasing ABC transporter expression.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.