هدف قرار دادن ناقل های ABC و غلبه بر مقاومت دارویی سلولهای سرطانی
Abstract
1- Introduction
2- Materials and methods
3- Results
4- Discussion
References
Abstract
Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4μ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4μ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer.
Introduction
Cancers have the ability to develop resistance to chemotherapy, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. Multidrug resistance is a phenomenon by which, after exposure to a chemotherapeutic agent, cancer cells develop resistance, and simultaneous cross-resistance, to a wide range of functionally and structurally unrelated chemotherapeutic drugs (1, 2). Intrinsic or acquired multidrug resistance is one of the main reasons for chemotherapy failure, leading to the recurrence of malignant tumors and ultimately, patient relapse or death (3). A variety of mechanisms have been attributed to multidrug resistance, such as enhanced drug efflux, increased DNA damage repair, reduced apoptosis, elevated autophagy, and/or altered drug metabolism (4-6). Previous studies have confirmed that multidrug resistance both in cancer cell lines and human tumor tissues is most often associated with the overexpression of the ATP-binding cassette (ABC) transporters (4, 7, 8). These ABC transporters are efflux pumps that transport various structurally unrelated and potentially dangerous substances out of the cells. They hydrolyze ATP for energy and actively pump drug components out of cells, leading to drug resistance. In these transporters, ABCB1 (also known as MDR1 or P-gp), ABCC1 (MRP1) and ABCG2 (BCRP1) play an important role in drug resistance in vivo (4, 7). Developing inhibitors of ABC transporters is an important approach to overcoming drug resistance. Extensive efforts have been made to develop inhibitors targeting ABC transporters, particularly ABCB1. However, no such agents have been developed successfully as was initially hoped.