Abstract
Multidrug resistance, mediated by members of the ATP-binding cassette (ABC) proteins superfamily, has become one of the biggest obstacles in conquering tumour progression. If the chemotherapy outcome is considered successful, when the primary tumour volume is decreased or completely abolished, modulation of ABC proteins activity is one of the best methods to overcome drug resistance. However, if a positive outcome is represented by no metastasis or, at least, elongation of remission-free time, then the positive effect of ABC proteins inhibition should be compared with the several side effects it causes, which may inflict cancer progression and decrease overall patient health. Clinical trials conducted thus far have shown that the tested ABC modulators add limited or no benefits to cancer patients, as some of them are merely toxic and others induce unwanted drug–drug interactions. Moreover, the inhibition of certain ABC members has been recently indicated as potentially responsible for increased fibroblasts migration. A better understanding of the complex role of ABC proteins in relation to cancer progression may offer novel strategies in cancer therapy.
Highlights
Cancer cells have developed several mechanisms that allow them to survive and progress in human organisms and resist anticancer therapy
It was demonstrated that the rs3742106 polymorphism in the 30 -UTR that enhances miR-3190-5p-mediated inhibition of ABCC4 expression is significantly related to the increased efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer [29]
The formation of lamellipodia, during cell direct migration, at the leading edge of mouse embryonic fibroblast cells and mouse breast tumour cells was shown to be inhibited by cAMP, which acts downstream of the small GTPase, Rac, whereas cGMP plays the opposite role in the modulation of lamellipodium formation [135]
Summary
Cancer cells have developed several mechanisms that allow them to survive and progress in human organisms and resist anticancer therapy. The overexpression of certain ABC proteins results in an apparent increase in carcinoma cell resistance to chemotherapeutics (e.g., paclitaxel, docetaxel, doxorubicin, cisplatin, topotecan, mitoxantrone (MTX), vincristine or vinblastine), leading to higher patient mortality. They protect cells through the active efflux of potentially harmful xenobiotics; inhibition of their activity is considered a standard clinical approach. Among all 48 members of seven families of the human ABC proteins (ABCA–ABCG), members of three (ABCB, ABCC and ABCG) are involved in the active efflux of anticancer drugs from the cell cytoplasm [1,5,6,7] They are known by alternative names: Multi Drug. All ABC transporters use ATP either to actively transport substrates or to stabilize the channel conformation
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