2. Academic Validation
  3. Bortezomib in Combination with Physachenolide C Reduces the Tumorigenic Properties of KRASmut/P53mut Lung Cancer Cells by Inhibiting c-FLIP

Bortezomib in Combination with Physachenolide C Reduces the Tumorigenic Properties of KRASmut/P53mut Lung Cancer Cells by Inhibiting c-FLIP

  • Cancers (Basel). 2024 Feb 4;16(3):670. doi: 10.3390/cancers16030670.
Thanigaivelan Kanagasabai 1,  Zerick Dunbar 2,  Salvador González Ochoa 3,  Tonie Farris 1,  Sivanesan Dhandayuthapani 4,  E M Kithsiri Wijeratne 5,  A A Leslie Gunatilaka 5,  Anil Shanker 3
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA.
  • 2 Department of Microbiology, Immunology & Physiology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.
  • 3 Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.
  • 4 Central Research Facility, Santosh Deemed to Be University, Ghaziabad 201009, UP, India.
  • 5 Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture, Life and Environmental Sciences, The University of Arizona, Tucson, AZ 85719, USA.
PMID: 38339421 DOI: 10.3390/cancers16030670
Abstract

Background: Defects in Apoptosis regulation are one of the classical features of Cancer cells, often associated with more aggressiveness and failure to therapeutic options. We investigated the combinatorial antitumor effects of a natural product, physachenolide C (PCC) and bortezomib, in KRASmut/P53mut lung Cancer cells and xenograft mice models.

Methods: The in vitro Anticancer effects of the bortezomib and PCC combination were investigated using cell viability, migration, and invasion assays in 344SQ, H23, and H358 cell lines. Furthermore, the effects of combination treatment on the critical parameters of cellular metabolism, including extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate of Cancer cells were assessed using Seahorse assay. Finally, the antitumor effect of the bortezomib (1 mg/kg) and PCC (10 mg/kg) combination was evaluated using xenograft mice models.

Results: Our data showed that the bortezomib-PCC combination was more effective in reducing the viability of lung Cancer cells in comparison with the individual treatments. Similarly, the combination treatment showed a significant inhibition of cell migration and invasion of Cancer cells. Additionally, the key anti-apoptotic protein c-FLIP was significantly inhibited along with a substantial reduction in the key parameters of cellular metabolism in Cancer cells. Notably, the bortezomib or PCC inhibited the tumor growth compared to the control group, the tumor growth inhibition was much more effective when bortezomib was combined with PCC in tumor xenograft mice models.

Conclusion: These findings demonstrate that PCC sensitizes Cancer cells to bortezomib, potentially improving the antitumor effects against KRASmut/P53mut lung Cancer cells, with an enhanced efficacy of combination treatments without causing significant side effects.

Keywords

KRAS; P53; bortezomib; c-FLIP; lung cancer; natural product; physachenolide C; withanolides.

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