The Ubiquitin-Proteasome Pathway and Resistance Mechanisms Developed Against the Proteasomal Inhibitors in Cancer Cells

(E-pub Ahead of Print)

Author(s): Azmi Yerlikaya*, Ertan Kanbur

Journal Name: Current Drug Targets

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Abstract:

Background: The ubiquitin-proteasome pathway is crucial for all cellular processes and is therefore a critical target for the investigation and development of novel strategies for cancer treatment. In addition, approximately 30% of newly synthesized proteins never attain their final conformations due to translational errors or defects in posttranslational modifications; therefore, they are also rapidly eliminated by the ubiquitin-proteasome pathway.

Objective: Here, we have tried to outline the recent findings deciphering the new molecular mechanisms involved in the regulation of ubiquitin-proteasome pathway as well as the resistance mechanisms developed against proteasome inhibitors in cell culture experiments as wells as in the clinical trials.

Results: Since cancer cells have higher proliferation rates and are more prone to the translational errors, they require the ubiquitin-proteasome pathway for selective advantage and sustained proliferation. Therefore, drugs targeting the ubiquitin-proteasome pathway are very promising agents for the treatment of both hematological and solid cancers.

Conclusions: A number of proteasome inhibitors are approved and used for the treatment of advanced and relapsed multiple myeloma. Unfortunately, drug resistance mechanisms may develop very fast within days of the start of to the proteasome inhibitor-treatment either due to the inherent or acquired resistance mechanisms under the selective drug pressure. However, a comprehensive understanding of the mechanisms leading to the proteasome inhibitor-resistance will eventually help design and development of novel strategies involving new drugs and/or drug combinations for the treatment of a number of cancers.

Keywords: Bortezomib, Cancer, Proteasome, Resistance, Ubiquitin

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Article Details

(E-pub Ahead of Print)
DOI: 10.2174/1389450121666200525004714
Price: $95

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