Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System

Abstract

Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZ-based therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib, Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of ubiquitin-proteasome system in the treatment of MM and other cancers.

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

“…Despite their notable success in MM and some other B‐lineage malignancies, PIs have to date proved relatively ineffective clinically in solid tumours (Dou & Zonder, 2014). MRZ displayed superior activity to BTZ in several solid tumour xenograft models and more potently impacted several hallmarks of cancer, including angiogenesis and invasion (reviewed in Potts et al , 2011), suggesting that a proteasome inhibitor with a broader spectrum of biochemical activity might be more active in solid tumours than those specific to the CT‐L subunit.…”

“…Several studies indicate that overexpression of catalytic subunits is the primary cellular response mechanism to BTZ treatment and may precede acquisition of β5 mutations (Franke et al , 2012; Niewerth et al , 2013), as well as increased β2 and β1 activity (Ruckrich et al , 2009). Given that both pan‐proteasome inhibitory activity (Britton et al , 2009) and irreversible binding to the proteasome subunits (Orlowski, 2013; Dou & Zonder, 2014) have been postulated to overcome BTZ resistance and provide prolonged activity, the unique pharmacological profile of MRZ may confer therapeutic advantage by irreversibly inhibiting more than one proteasomal activity (reviewed in Kale & Moore, 2012). …”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…The mechanism of action of bortezomib (also known as PS‐341) involves the specific inhibition of proteasome, which is responsible for cytotoxicity and apoptosis in cancer cells (Holkova and Grant 2012; Dou and Zonder 2014). Indeed, proteasome inhibition secondarily leads to ER stress, ROS production, and activation of JNK and other signaling pathways inducing cell death (Lee et al.…”

Combined chemical–genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma

“…The protein homeostasis ("proteostasis") network that operates in cancer cells offers targets for therapeutic development, such as the proteasome and specific protein chaperones (2,3). For example, the heat-shock protein 90 kDa (HSP90) chaperone maintains the stability of some mutant oncoproteins and permits the outgrowth of drug-resistant cells, fueling the development of small molecule HSP90 inhibitors as anticancer agents (4).…”