Genomic alterations and enormous monoclonal immunoglobulin production cause multiple myeloma to heavily depend on proteostasis mechanisms, including protein folding and degradation. These findings support the use of proteasome inhibitors for treating multiple myeloma and mantle cell lymphoma. Myeloma treatment has evolved, especially with the availability of new drugs, such as proteasome inhibitors, into therapeutic strategies for both frontline and relapsed/refractory disease settings. However, proteasome inhibitors are generally not effective enough to cure most patients. Natural resistance and eventual acquired resistance led to relapsed/refractory disease and poor prognosis. Advances in the understanding of cellular proteostasis and the development of innovative drugs that also target other proteostasis network components offer opportunities to exploit the intrinsic vulnerability of myeloma cells. This review outlines recent findings on the molecular mechanisms regulating cellular proteostasis pathways, as well as resistance, sensitivity, and escape strategies developed against proteasome inhibitors and provides a rationale and examples for novel combinations of proteasome inhibitors with FDA-approved drugs and investigational drugs targeting the NRF1 (NFE2L1)-mediated proteasome bounce-back response, redox homeostasis, heat shock response, unfolding protein response, autophagy, and VCP/p97 to increase proteotoxic stress, which can improve the efficacy of antimyeloma therapy based on proteasome inhibitors.

• Keywords
• Autophagy, Heat shock response, Proteasome bounce-back response, Redox homeostasis, UPR, VCP/p97,
• MeSH
• Drug Resistance, Neoplasm MeSH
• Proteostasis * drug effects   MeSH
• Proteasome Inhibitors * therapeutic use   pharmacology   MeSH
• Humans MeSH
• Multiple Myeloma * drug therapy   metabolism   MeSH
• Antineoplastic Agents * therapeutic use   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Proteasome Inhibitors * MeSH
• Antineoplastic Agents * MeSH

DDI2 is an aspartic protease that cleaves polyubiquitinated substrates. Upon proteotoxic stress, DDI2 activates the transcription factor TCF11/NRF1 (NFE2L1), crucial for maintaining proteostasis in mammalian cells, enabling the expression of rescue factors, including proteasome subunits. Here, we describe the consequences of DDI2 ablation in vivo and in cells. DDI2 knock-out (KO) in mice caused embryonic lethality at E12.5 with severe developmental failure. Molecular characterization of embryos showed insufficient proteasome expression with proteotoxic stress, accumulation of high molecular weight ubiquitin conjugates and induction of the unfolded protein response (UPR) and cell death pathways. In DDI2 surrogate KO cells, proteotoxic stress activated the integrated stress response (ISR) and induced a type I interferon (IFN) signature and IFN-induced proliferative signaling, possibly ensuring survival. These results indicate an important role for DDI2 in the cell-tissue proteostasis network and in maintaining a balanced immune response.

• Keywords
• Biological sciences, Developmental biology, Immune respons,
• Publication type
• Journal Article MeSH

BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 * metabolism   antagonists & inhibitors   MeSH
• Apoptosis drug effects   MeSH
• Bortezomib * pharmacology   MeSH
• HIV Protease Inhibitors * pharmacology   MeSH
• Proteasome Inhibitors pharmacology   MeSH
• Humans MeSH
• Lopinavir * pharmacology   MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins antagonists & inhibitors   metabolism   MeSH
• Nelfinavir * pharmacology   MeSH
• Oligopeptides * pharmacology   MeSH
• ATP Binding Cassette Transporter, Subfamily B metabolism   MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   MeSH
• Unfolded Protein Response * drug effects   MeSH
• Endoplasmic Reticulum Stress drug effects   MeSH
• Drug Synergism * MeSH
• Triple Negative Breast Neoplasms * drug therapy   pathology   MeSH
• X-Box Binding Protein 1 metabolism   genetics   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 * MeSH
• ABCB1 protein, human MeSH Browser
• ABCG2 protein, human MeSH Browser
• Bortezomib * MeSH
• carfilzomib MeSH Browser
• HIV Protease Inhibitors * MeSH
• Proteasome Inhibitors MeSH
• Lopinavir * MeSH
• Neoplasm Proteins MeSH
• Nelfinavir * MeSH
• Oligopeptides * MeSH
• ATP Binding Cassette Transporter, Subfamily B MeSH
• XBP1 protein, human MeSH Browser
• X-Box Binding Protein 1 MeSH

Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.

• MeSH
• Antiviral Agents pharmacology   therapeutic use   MeSH
• COVID-19 * MeSH
• HIV Infections * drug therapy   MeSH
• Humans MeSH
• SARS-CoV-2 MeSH
• Viral Proteases MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• nirmatrelvir and ritonavir drug combination MeSH Browser
• Viral Proteases MeSH