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

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  • معلومة اضافية
    • المصدر:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • الموضوع:
      Carcinoma, Non-Small-Cell Lung*/drug therapy ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/therapeutic use ; Multiple Myeloma*/pathology ; Lung Neoplasms*/drug therapy; Humans ; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Nelfinavir/pharmacology ; Nelfinavir/therapeutic use ; Proteasome Inhibitors/pharmacology ; Cell Line, Tumor ; Proteasome Endopeptidase Complex ; Apoptosis
    • نبذة مختصرة :
      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.
      (© 2023. The Author(s).)
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    • الرقم المعرف:
      69G8BD63PP (Bortezomib)
      HO3OGH5D7I (Nelfinavir)
      0 (Proteasome Inhibitors)
      72X6E3J5AR (carfilzomib)
      0 (Antineoplastic Agents)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
    • الموضوع:
      Date Created: 20230318 Date Completed: 20230321 Latest Revision: 20230418
    • الموضوع:
      20230418
    • الرقم المعرف:
      PMC10023769
    • الرقم المعرف:
      10.1038/s41598-023-31400-6
    • الرقم المعرف:
      36932175