School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
Cancer Chemother Pharmacol. 2010 Aug;66(3):585-96. doi: 10.1007/s00280-009-1200-9. Epub 2009 Dec 18.
The development of multi-drug resistance (MDR) due to the expression of members of the ATP binding cassette (ABC) transporter family is a major obstacle in cancer treatment. The broad range of substrate specificities associated with these transporters leads to the efflux of many anti-cancer drugs from tumour cells. Therefore, the development of new chemotherapeutic agents that are not substrates of these transporters is important. We have recently demonstrated that some members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds are microtubule-depolymerising agents that potently induce apoptosis in several cancer cell lines and impair growth of mouse breast tumours. The aim of this current study was to establish whether PBOXs were capable of inducing apoptosis in cancer cells expressing either P-glycoprotein or breast cancer resistance protein (BCRP), two of the main ABC transporters associated with MDR.
We performed in vitro studies to assess the effects of PBOXs on cell proliferation, cell cycle and apoptosis in human cancer cell lines and their drug-resistant substrains expressing either P-glycoprotein or BCRP. In addition, we performed a preliminary molecular docking study to examine interactions between PBOXs and P-glycoprotein.
We established that three representative PBOXs, PBOX-6, -15 and -16 were capable of inducing apoptosis in drug-resistant HL60-MDR1 cells (expressing P-glycoprotein) and HL60-ABCG2 cells (expressing BCRP) with similar potencies as in parental human promyelocytic leukaemia HL60 cells. Likewise, resistance to PBOX-6 and -16 was not evident in P-glycoprotein-expressing A2780-ADR cells in comparison with parent human ovarian carcinoma A2780 cells. Finally, we deduced by molecular docking that PBOX-6 is not likely to form favourable interactions with the substrate binding site of P-glycoprotein.
Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.
由于 ATP 结合盒（ABC）转运蛋白家族成员的表达而导致的多药耐药（MDR）的发展是癌症治疗的主要障碍。这些转运蛋白具有广泛的底物特异性，导致许多抗癌药物从肿瘤细胞中流出。因此，开发不是这些转运体底物的新化疗药物很重要。我们最近证明，一系列新型吡咯并[1,5-b]苯并恶嗪（PBOX）化合物的某些成员是微管解聚剂，可在几种癌细胞系中强烈诱导细胞凋亡，并抑制小鼠乳腺癌的生长。本研究的目的是确定 PBOX 是否能够在表达 P-糖蛋白或乳腺癌耐药蛋白（BCRP）的癌细胞中诱导细胞凋亡，这两种 ABC 转运蛋白与 MDR 密切相关。
我们进行了体外研究，以评估 PBOX 对表达 P-糖蛋白或 BCRP 的人癌细胞系及其耐药亚系的细胞增殖、细胞周期和细胞凋亡的影响。此外，我们进行了初步的分子对接研究，以检查 PBOX 与 P-糖蛋白之间的相互作用。
我们确定了三种代表性的 PBOX（PBOX-6、-15 和-16）能够在表达 P-糖蛋白的 HL60-MDR1 细胞和表达 BCRP 的 HL60-ABCG2 细胞中诱导细胞凋亡，其效力与亲本人早幼粒细胞白血病 HL60 细胞相似。同样，在表达 P-糖蛋白的 A2780-ADR 细胞中，PBOX-6 和 -16 的耐药性与亲本人卵巢癌细胞 A2780 细胞相比并不明显。最后，我们通过分子对接推断出 PBOX-6 不太可能与 P-糖蛋白的底物结合位点形成有利的相互作用。
我们的结果表明，促凋亡的 PBOX 化合物可能是治疗 P-糖蛋白或 BCRP 相关 MDR 癌症的潜在候选药物。
