The therapeutic potential of targeting ABC transporters to combat multi-drug resistance

Abstract

Most disseminated cancers remain fatal despite the availability of a variety of conventional and novel treatments including surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy. A major factor responsible for the failure of chemotherapy in the treatment of cancer is the development of multidrug resistance (MDR). The overexpression of various ABC transporters in cancer cells can efficiently remove the anticancer drug from the cell, thus causing the drug to lose its effect. Areas covered: In this review, we summarised the ongoing research related to the mechanism, function, and regulation of ABC transporters. We integrated our current knowledge at different levels from molecular biology to clinical trials. We also discussed potential therapeutic strategies of targeting ABC transporters to reverse MDR in cancer cells. Expert opinion: Involvement of various ABC transporters to cancer MDR lays the foundation for developing tailored therapies that can overcome MDR. An ideal MDR reversal agent should have broad-spectrum ABC-transporter inhibitory activity, be potent, have good pharmacokinetics, have no trans-stimulation effects, and have low or no toxicity. Alternatively, nanotechnology-based drug delivery systems containing both the cytotoxic drug and reversing agent may represent a useful approach to reversing MDR with minimal off-target toxicity.

Control of metabolite efflux in microbial cell factories: current advances and future prospects

“…for cancer chemotherapy (e.g. [128][129][130]). In microbes, where they have also presumably evolved to remove environmental toxins that had been taken up [131], they can play a leading role in microbial resistance to anti-infectives [132][133][134][135][136][137][138][139].…”

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

“…Several ABC transporters, such as ABCG2/BCRP1 and ABCB1/MDR1, play major roles in drug resistance in tumor cells . It has been previously reported that a panel of indolocarbazole protein kinase inhibitors, including midostaurin, were able to inhibit the transport activity of ABCG2 .…”

“…However, advanced sarcomas often show resistance to doxorubicin, mainly through the overexpression of members of ATP binding cassette (ABC) transmembrane family of transporters which act as efflux pumps for anti‐cancer drugs . Therefore, the development of therapeutic strategies able to prevent drug resistance would undoubtedly improve current sarcoma treatments …”

“…6 Therefore, the development of therapeutic strategies able to prevent drug resistance would undoubtedly improve current sarcoma treatments. 7,8 The phosphotidylinositol-3 0 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is abnormally activated in many sarcomas and alterations in several components of this axis have been correlated with poor clinical outcome. [9][10][11][12] Specifically, myxoid and round cell liposarcomas (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, frequently show oncogenic events, such as mutations in PI3KCA or overactivation of insulin-like growth factor I receptor (IGF1R) or SRC signaling, which provoke an abnormal activation of these route.…”

Fighting tubulin-targeting anticancer drug toxicity and resistance

“…To overcome ABC transporter-mediated resistance, various approaches have been exploited, including the development of drugs that specifically inhibit ABC family members. However, up to now, most of the phase III clinical trials with such inhibitors have failed (Robert & Jarry 2003, Shukla et al 2011, Bugde et al 2017. Interestingly, it has been recently reported that the antiandrogens bicalutamide and enzalutamide inhibit ABCB1 efflux activity.…”