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 post-translational modifications; therefore, they are also
rapidly eliminated by the ubiquitin-proteasome pathway.
Objective: Here, an effort was made 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 and in the clinical
Results: Since cancer cells have higher proliferation rates and are more prone to translational errors,
they require the ubiquitin-proteasome pathway for selective advantage and sustained proliferation.
Therefore, drugs targeting the ubiquitin-proteasome pathway are promising agents for the treatment of
both hematological and solid cancers.
Conclusion: 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 the proteasome inhibitor-treatment either due to the inherent or acquired resistance
mechanisms under selective drug pressure. However, a comprehensive understanding of the
mechanisms leading to the proteasome inhibitor-resistance will eventually help the design and development
of novel strategies involving new drugs and/or drug combinations for the treatment of a number