Dept. Biochemical Sciences, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy.
Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Dept. Biochemical Sciences, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy.
Drug Resist Updat. 2017 May;32:23-46. doi: 10.1016/j.drup.2017.10.003. Epub 2017 Oct 16.
The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR.
耐药性的发展仍然是癌症治疗的主要障碍。广泛的 ATP 依赖性外排泵的过度表达，特别是 ABCB1（P-糖蛋白或 MDR1），是多种癌症化疗药物的一种众所周知的耐药机制，例如紫杉醇、蒽环类药物、长春花生物碱和表鬼臼毒素，这已被大量发表的论文证明，无论是在肿瘤细胞系还是在各种肿瘤中，包括各种实体瘤和血液恶性肿瘤。在培养的肿瘤细胞或体内肿瘤中反复或甚至单次剂量使用抗肿瘤药物（如紫杉醇和多柔比星）治疗后，已证明 ABCB1 拷贝数增加，这是由于 7q11.2-21 位染色体扩增事件导致的，导致明显的 P-糖蛋白过度表达和多药耐药（MDR）。然而，很明显，其他机制，如单核苷酸多态性（SNP）和表观遗传修饰，在 ABCB1 和其他 MDR 外排泵的过度表达中也发挥了作用。然而，尽管设计了四代 ABCB1 抑制剂，并积累了大量关于 ABC 转运蛋白的生物化学和底物特异性的信息，但将这些丰富的知识从实验室转化到临床实践却出乎意料地困难。许多研究表明，在紫杉醇和蒽环类药物以及其他化疗药物反复治疗细胞培养物或肿瘤的方案中，观察到 ABCB1 基因座周围一系列基因的扩增和/或过度表达。因此，其他蛋白质水平的改变可能有助于建立 MDR 表型，并导致临床结局不佳。因此，该 ABCB1 扩增子中包含的基因，包括 ABCB4、SRI、DBF4、TMEM243 和 RUNDC3B，在许多癌症中过度表达，尤其是在 MDR 肿瘤中，而 TP53TG1 和 DMTF1 是真正的肿瘤抑制因子。这篇综述描述了这些基因在癌症中的作用，特别是在获得 MDR 中的作用，阐明了属于同一 ABCB1 扩增子区域的基因在转录调控（共扩增/抑制）方面的可能联系，并描述了它们在肿瘤生物学中的新出现的贡献以及克服癌症 MDR 的可能策略。
