Abstract
The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.
Highlights
Despite progress being made in cancer treatment, patients are still failing therapy, which results in progression of the disease, relapse and an overall reduced patient survival
We propose a shift of focus from the role played by ATP binding cassette (ABC) transporters in multidrug resistance to the specific ABC transporter functions in Cancer Stem Cells (CSCs)
One of the limitations is the fact that research has focused on a handful of proteins, namely ATP-binding cassette subfamily-B member 1 (ABCB1), ABCC1 and ATP-binding cassette subfamily-G member 2 (ABCG2)
Summary
Despite progress being made in cancer treatment, patients are still failing therapy, which results in progression of the disease, relapse and an overall reduced patient survival. A number of molecular mechanisms can be involved in cancer chemoresistance, such as increased expression of transporters that can extrude anticancer drugs, decreased drug uptake into the cell, activation of detoxification mechanisms, and malfunctioning apoptotic pathways [3,4] This intrinsic resistance of CSCs to anti-cancer therapy may be the source of disease progression and relapse. Some cancers are organized in an arrangement where tumorigenic CSCs differentiate into progeny, supporting the CSC model [3] According to this model, tumours are a heterogeneous mixture of genetically distinct subclones that contribute to the functional and phenotypic heterogeneity of the tumour. Members of the ABC transporter superfamily have a broad spectrum of physiological activity including detoxification, ATP-binding cassette subfamily-B member 1, multidrug resistance protein 1, permeability glycoprotein (ABCB1/MDR1/P-gp), ATP-binding cassette subfamily-C member 1, multidrug resistance-associated protein 1 (ABCC1/MRP1), defense against oxidative stress and xenobiotics (ABCCs and MRPs), lipid metabolism (MDR3, ABCA and ABCG families), and antigen presentation ATP-binding cassette subfamily-B member 2 and 3, antigen peptide transporter 1 and 2 (ABCB2/TAP1 and ABCB3/TAP2) [43]
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