Home Blog of Signal Transduction Ubiquitin COVID-19 The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma

Chemotherapy resistance is still a major problem in the treatment of patients with non-small-cell-lung carcinoma (NSCLC), and novel concepts for the induction of cytotoxicity in NSCLC are highly warranted. Proteotoxicity, the induction of cytotoxicity by targeting the ubiquitin proteasome system, represents an appealing innovative strategy. The combination of the proteasome inhibitor bortezomib (BTZ) and the proteotoxic stress-inducing HIV drug nelfinavir (NFV) synergistically induces proteotoxicity and shows encouraging preclinical efficacy in NSCLC. The second-generation proteasome inhibitor carfilzomib (CFZ) is superior to BTZ and overcomes BTZ resistance in multiple myeloma patients. Here, we show that CFZ together with NFV is superior to the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity through the accumulation of excess proteasomal substrate protein in NSCLC in vitro and ex vivo. Interestingly, NFV increases the intracellular availability of CFZ through inhibition of CFZ export from NSCLC cells that express multidrug resistance (MDR) protein. Combining CFZ with NFV may therefore represent a future treatment option for NSCLC, which warrants further investigation.

 

Comments：

The statement highlights the challenges in treating non-small-cell-lung carcinoma (NSCLC) due to chemotherapy resistance and the need for novel strategies to induce cytotoxicity. One such strategy is proteotoxicity, which involves targeting the ubiquitin proteasome system. The combination of the proteasome inhibitor bortezomib (BTZ) and the HIV drug nelfinavir (NFV) has shown promising results in inducing proteotoxicity in NSCLC. However, the second-generation proteasome inhibitor carfilzomib (CFZ) has been found to be superior to BTZ and can overcome BTZ resistance in multiple myeloma patients.

The statement further reports that CFZ, when combined with NFV, is more effective than the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity in NSCLC in vitro and ex vivo. Moreover, the statement suggests that NFV can increase the intracellular availability of CFZ by inhibiting its export from NSCLC cells expressing multidrug resistance (MDR) protein. Thus, combining CFZ with NFV may represent a promising future treatment option for NSCLC, which requires further investigation.

Related Products

Cat.No. Product Name Information
S2853 Carfilzomib (PR-171) Carfilzomib (PR-171) is an irreversible proteasome inhibitor with IC50 of <5 nM in ANBL-6 cells, displayed preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, but little or no effect on the PGPH and T-L activities. Carfilzomib activates prosurvival autophagy and induces cell apoptosis.

Related Targets

COVID-19 Apoptosis related Proteasome Autophagy