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-X(L) 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.

Fig. (1)

The ubiquitin-proteasome pathway. The ubiquitination of target proteins is mediated by Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3) enzymes. Substrate proteins tagged with a multiple-ubiquitin chain are then degraded by the 26S proteasome which is composed of a 20S catalytic core and two 19S subunits.

Fig. (2)

Chemical structure, nucleophilic susceptibility of bortezomib and its computational docking in the β5 subunit of the proteasome. A, The chemical structure of bortezomib. B, Nucleophilic susceptibility of bortezomib analyzed using CAChe software. Higher susceptibility was shown mainly at the boron in bortezomib. This highly susceptible atom for nucleophilic attack was shown by a red “bull’s-eye”. C, Bortezomib was docked into the β5 subunit of the proteasome by using AutoDock 3.0 and visualized by using PyMol v 0.99. The resultant image showed that bortezomib fits into and blocks the S1 pocket of β5 subunit of the proteasome.

Fig. (3)

Inactivation of NF-κB pathway by bortezomib. In response to external stress, the IκB becomes phosphorylated by IKK and degraded by the proteasome. With the degradation of IκB, the NF-κB complex then translocates into the nucleus and promotes transcription of a series of pro-survival genes. Proteasome inhibition prevents the activation of NF-κB and increases the susceptibility of malignant cells to chemotherapeutic drugs.