Bortezomib as the First Proteasome Inhibitor Anticancer Drug: Current Status and Future Perspectives

Abstract

Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. Based on positive preclinical and clinical studies, bortezomib was subsequently approved for the clinical use as a front-line treatment for newly diagnosed multiple myeloma patients and for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this drug has become the staple of treatment. The approval of bortezomib by the US Food and Drug Administration (FDA) represented a significant milestone as the first proteasome inhibitor to be implemented in the treatment of malignant disease. Bortezomib has shown a positive clinical benefit either alone or as a part of combination therapy to induce chemo-/radio-sensitization or overcome drug resistance. One of the major mechanisms of bortezomib associated with its anticancer activity is through upregulation of NOXA, which is a proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of Bcl-2 subfamily Bcl-XL and Bcl-2, and result in apoptotic cell death in malignant cells. Another important mechanism of bortezomib is through suppression of the NF-κB signaling pathway resulting in the down-regulation of its anti-apoptotic target genes. Although the majority of success achieved with bortezomib has been in hematological malignancies, its effect toward solid tumors has been less than encouraging. Additionally, the widespread clinical use of bortezomib continues to be hampered by the appearance of dose-limiting toxicities, drug-resistance and interference by some natural compounds. These findings could help guide physicians in refining the clinical use of bortezomib, and encourage basic scientists to generate next generation proteasome inhibitors that broaden the spectrum of efficacy and produce a more durable clinical response in cancer patients. Other desirable applications for the use of proteasome inhibitors include the development of inhibitors against specific E3 ligases, which act at an early step in the ubiquitin-proteasome pathway, and the discovery of less toxic and novel proteasome inhibitors from natural products and traditional medicines, which may provide more viable drug candidates for cancer chemoprevention and the treatment of cancer patients in the future.

Chemotherapy‐induced neuropathies—a growing problem for patients and health care providers

“…It is a very potent drug, often used when other antineoplastic agents fail (Chen, Frezza, Schmitt, Kanwar, & Dou, 2011; Richardson, Hideshima, & Anderson, 2003). Peripheral nerve changes and polyneuropathy symptoms affect 20–30% of all bortezomib‐treated patients and are manifested as neuropathic pain of toes and/or fingers, tingling and burning sensations, and muscle wasting.…”

An ubiquitin-binding molecule can work as an inhibitor of ubiquitin processing enzymes and ubiquitin receptors

“…Therefore, the ubiquitin signaling pathway, and more specifically, the enzymes involved in both ubiquitination, deubiquitination and proteasome, have been considered a good therapeutic target, and many inhibitors targeting specific enzymes in ubiquitin pathways have been developed as drug candidates for various diseases [16,19]. In particular, Bortezomib, an ubiquitin proteasome system (UPS) inhibitor approved by the US FDA as a cancer drug, supports the druggability of the ubiquitin signaling [20,21]. While the enzymes in the ubiquitin pathways have been recognized as druggable targets [22][23][24], ubiquitin, the main agent of this signaling pathway, has been generally considered as non-druggable.…”

Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

“…Bortezomib (BTZ, N-acyl-pseudo dipeptidyl boronic acid) reversibly binds to PSMB5 [26], the chymotrypsin-like β5 subunit of the catalytic chamber of the 20S proteasome [27]. BTZ was the first clinically approved proteasome inhibitor and is currently in use for treating multiple myeloma and other human malignancies.…”