<p class="first" id="d3525449e172">Drug resistance is a major obstacle in the field
of pre-clinical and clinical therapeutics.
The development of novel technologies and targeted therapies have yielded new modalities
to overcome drug resistance, but multidrug resistance (MDR) remains one of the major
challenges in the treatment of cancer. The ubiquitin-proteasome system (UPS) has a
central role in regulating the levels and activities of a multitude of proteins as
well as regulation of cell cycle, gene expression, response to oxidative stress, cell
survival, cell proliferation and apoptosis. Therefore, inhibition of the UPS could
represent a novel strategy for the treatment and overcoming of drug resistance in
chemoresistant malignancies. In 2003, bortezomib was approved by the FDA for the treatment
of multiple myeloma (MM). However, due to its limitations, second generation proteasome
inhibitors (PIs) like carfilzomib, ixazomib, oprozomib, delanzomib and marizomib were
introduced which displayed clinical activity in bortezomib-resistant tumors. Past
studies have demonstrated that proteasome inhibition potentiates the anti-cancer efficacy
of other chemotherapeutic drugs by: i) decreasing the expression of anti-apoptotic
proteins such as TNF-α and NF-kB, ii) increasing the levels of Noxa, a pro-apoptotic
protein, iii) activating caspases and inducing apoptosis, iv) degrading the pro-survival
protein, induced myeloid leukemia cell differentiation protein (MCL1), and v) inhibiting
drug efflux transporters. In addition, the mechanism of action of the immunoproteasome
inhibitors, ONX-0914 and LU-102, suggested their therapeutic role in the combination
treatment with PIs. In the current review, we discuss various PIs and their underlying
mechanisms in surmounting anti-tumor drug resistance when used in combination with
conventional chemotherapeutic agents.
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