Role of ATP-Binding Cassette Transporter Proteins in CNS Tumors: Resistance- Based Perspectives and Clinical Updates

Abstract

: Despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge for CNS tumors. The failure of complete eradication of CNS tumors has been correlated with the existence of several factors including over expression of transporter proteins. To date, 49 ABC-transporter proteins (ABC-TPs) are reported in humans, and the evidence of their strong association with chemotherapeutics’ influx, dissemination, and efflux in CNS tumors, is growing. Research studies in CNS tumor are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters’ interaction, our research approaches are streamlining the ABC-TPs’ roles in cancers and multidrug resistance. Potential ABC-TPs’ inhibitors for better clinical outcomes in CNS tumors have emerged. These include members of EZH2 inhibitors, which exhibit disparate level of selectivity for being a substrate for ABCB1 and ABCG2. Elacridar was shown to enhance chemo-sensitivity of Dasatanib and Imatinib in various glioma models. Tariquidar has improved Temozolomide’s effectiveness in CNS tumors. Although these inhibitors were shown to be effective in preclinical settings, their significant clinical outcomes have not been promising in clinical trials. Molecular evaluations of ABC-TPs and their drug-interactions are being pursued in various research labs, including ours, in an effort to better comprehend their biological mechanisms that are utilised for drug resistance, and to develop novel strategies to upsurge the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve the clinical outcomes.

Novel Sigma-2 receptor ligand A011 overcomes MDR in adriamycin-resistant human breast cancer cells by modulating ABCB1 and ABCG2 transporter function

“…The ABC transporter superfamily is one of the largest families of transmembrane proteins, consisting of 49 ABC transporter members ( Asif et al, 2020 ). Structurally, ABC transporters are characterized by a common structure: two nucleotide-binding domains (NBDs), which can bind and hydrolyze ATP, and two transmembrane domains (TMDs), which utilize the energy provided by ATP hydrolysis to transport substrates outside the cell.…”

ABCC10-mediated Oxaliplatin resistance in colorectal cancer cells was alleviated by intense endoplasmic reticulum stress (ERS) / IRE1α

“…Over-expressed in several chemo-resistant cancer types, ABC transporters confer resistance to various chemotherapeutics through rapid elimination, thereby decreasing their overall accumulation within the cancer cells [6][7][8][9]. Inhibitors of ABC transporters were developed with the demand, which, however, initially showed promise but failed clinically, due to high toxicity and other undesired side effects [10][11][12].…”