Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later

Abstract

Bortezomib is a dipeptidyl boronic acid that selectively inhibits the ubiquitin proteasome pathway, which plays a role in the degradation of many intracellular proteins. It is the first-in-class selective and reversible inhibitor of the 26S proteasome, with antiproliferative and antitumor activity. It exerts its anti-neoplastic action mainly via the inhibition of the nuclear factor-κB pathway components associated with cell proliferation, apoptosis, and angiogenesis. The drug has revolutionized the treatment of multiple myeloma and, more recently, mantle cell lymphoma. In 2003, bortezomib received accelerated approval from the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma and in 2008 for patients with previously untreated multiple myeloma. In 2006, bortezomib was approved for the treatment of refractory/relapsed mantle cell lymphoma and, in 2014, for previously untreated mantle cell lymphoma. Bortezomib has also demonstrated clinical efficacy both as a single drug and in combination with other agents in light chain amyloidosis, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, and peripheral T-cell lymphomas. Furthermore, continued clinical studies are required to confirm its value for patients with indolent and aggressive B-cell non-Hodgkin lymphomas and acute leukemias.

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

“…[46] Bortezomib (Btz) was used at 2 nM, a dosage corresponding to the lowest effective dose that produced only a moderate doserelated reduction of cell viability/mitochondrial activity, due to its well-known pro-apoptotic effect on cancer cells (see Fig-ure S10 of Supporting Information). [47] The pre-treatment with the proteasome inhibitor completely abolished the protective activity of the two pyrazolones against Aβ42 toxicity. We observed that the co-treatment with Btz and Aβ42 did not produce neither synergistic nor additive toxic effects since cell viability was decreased down to 59 %, a value which is very similar to that measured in the presence of only Aβ42 (63 %).…”

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

“…Bortezomib is a reversible inhibitor of the proteasome 26S subunit, whose targeting turned out to be a feasible strategy in several haematological malignancies [66]. Recently, it has been shown that CX-4945 enhanced bortezomib-induced apoptosis in a panel of both B-and T-ALL cell lines, as well as in primary ALL blasts from paediatric patients [39].…”

Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency

“…For example, the pharmacologic proteasome inhibitor (PI) BTZ improves clinical outcomes in patients with multiple myeloma (MM) (37-41). However, a subset of these patients develop resistance to this PI after a prolonged period of therapy (42)(43)(44)(45)(46). The therapeutic effects of BTZ arise partially from blocking proteasomal degradation of IκBα (38), akin to the mechanism of NF-κB suppression reported here.…”