Publikation

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

Wissenschaftlicher Artikel/Review - 17.03.2023

Bereiche
PubMed
DOI
Kontakt

Zitation
Besse L, Kraus M, Besse A, Driessen C, Tarantino I. The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma. Sci Rep 2023; 13:4411.
Projekt
Art
Wissenschaftlicher Artikel/Review (Englisch)
Zeitschrift
Sci Rep 2023; 13
Veröffentlichungsdatum
17.03.2023
eISSN (Online)
2045-2322
Seiten
4411
Kurzbeschreibung/Zielsetzung

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.