Cancer Stem Cell and ATP-Binding Cassette: Which Role in Chemoresistance?

Abstract

Chemoresistance is mediated through a variety of cellular alterations including, among others, reduced drug accumulation, decreased levels of protein targets, change in drugs metabolism, and break down of apoptotic signaling. The capability to acquire resistance to multiple compounds by cancer stem cells (CSCs), called multidrug resistance (MDR), is attributed to overexpression of ATP-binding cassette (ABC) transporters that extrude several substrates from the cell using ATP as driving force. ABC proteins are involved in the exclusion from the cells of several physiological compounds and/or xenobiotics. Three members of the ABC protein superfamily, ABCB1, ABCC1, and ABCG2 which play a major role in mediating clinical development of the MDR phenotype are also implicated in protection from chemotherapy of CSCs. In brief, the most intriguing characteristic of CSCs is their ability to acquire resistance to multiple anticancer agents that is often mediated by overexpression of ABC transporters which remove drugs out of the cell against a concentration gradient. Modulation of ABC transporters, using inhibitors in a combination therapy with cytostatic agents, could be a winning strategy to mitigate CSCs’ chemoresistance and open the door to apoptotic pathways of these cells in order to prevent relapse of tumor metastases.