Enhancing activity and overcoming chemoresistance in hematologic malignancies with bortezomib: preclinical mechanistic studies

Abstract

This review indicates the potential utility of proteasome inhibition for substantially enhancing activity of other therapeutic approaches. It explains the mechanisms responsible for the observed clinical activity of bortezomib-based regimens and elucidates novel therapeutic approaches through identification of combinations of agents with complimentary mechanisms of action.

Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes

“…The combination of LBH589, vorinostat, or romidepsin with bortezomib has been shown to inhibit aggresome formation and result in apoptosis, probably as a result of accumulation of toxic proteins that are not subsequently packaged for disposal via the aggresome/autophagy pathway. 13,[19][20][21][22][23][24][25] It has been presumed that accumulation of unpackaged misfolded proteins is toxic to cells and that packaging of these proteins into aggresomes results in their disposal and therefore protects the cell from toxic injury. However, the pathway for catabolism of proteins via autophagy may be more complex.…”

Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer

“…They act through a variety of mechanisms, including p53 stabilization, alterations in gene expression, and inhibition of caspase degradation, among many others (Eldridge and O'Brien, 2009). Proteasome inhibitors have also been shown to overcome chemotherapy and radiotherapy resistance through inhibition of IκB degradation (Chen et al, 2011;Reddy and Czuczman, 2010;Russo, 2001). …”

Proteasome inhibitors in multiple myeloma: 10 years later

“…Bortezomib directly induces apoptosis of tumor cells, inhibits the activation of NF-B in cells and in the tumor microenvironment, reduces adherence of myeloma cells to bone marrow stromal cells, blocks production and intracellular signaling of IL-6 in myeloma cells, stops the production and expression of proangiogenic mediators, and overcomes defects in apoptotic regulators, such as Bcl-2 overexpression and alterations in tumor suppressor p53. 11,12 In addition, proteasome inhibition with bortezomib has been shown to induce the endoplasmic reticulum stress response, associated with disruption of the unfolded protein response, an important aspect of the mechanism of action of proteasome inhibition in MM because of the high production of immunoglobulins by MM cells. 13 These mechanisms of action of proteasome inhibition have provided the rationale for the combination of bortezomib and other PIs with numerous chemotherapeutic and targeted agents [12][13][14] ; for example, the disruption of protein quality control and the consequent activation of aggresomal degradation of misfolded proteins have provided a strong rationale for the combination of PIs and histone deacetylase inhibitors.…”

“…11,12 In addition, proteasome inhibition with bortezomib has been shown to induce the endoplasmic reticulum stress response, associated with disruption of the unfolded protein response, an important aspect of the mechanism of action of proteasome inhibition in MM because of the high production of immunoglobulins by MM cells. 13 These mechanisms of action of proteasome inhibition have provided the rationale for the combination of bortezomib and other PIs with numerous chemotherapeutic and targeted agents [12][13][14] ; for example, the disruption of protein quality control and the consequent activation of aggresomal degradation of misfolded proteins have provided a strong rationale for the combination of PIs and histone deacetylase inhibitors. 13 As a result of its mechanisms of action, bortezomib has also been associated with increased bone formation and osteoblastic activity, and decreased bone resorption and osteoclastic activity.…”