ALTERATIONS IN APOPTOSIS-ASSOCIATED GENE EXPRESSIONS IN LUNG CANCER CELLS IN THE PRESENCE OF IXAZOMIB AND GIVINOSTAT

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Kaya Tilki E.

14th International Symposium on Pharmaceutical Sciences (ISOPS), Ankara, Turkey, 25 - 28 June 2024, pp.364, (Full Text)

  • Publication Type: Conference Paper / Full Text
  • City: Ankara
  • Country: Turkey
  • Page Numbers: pp.364
  • Anadolu University Affiliated: Yes

Abstract

Introduction: Proteasome inhibitors and histone deacetylase (HDAC) inhibitors hold promise in lung cancer treatment by enhancing cancer cell sensitivity to therapy. Specifically, combining bortezomib, a proteasome inhibitor, with HDAC inhibitors has been shown to sensitize non-small cell lung cancer cells (1). This combined therapy exhibits heightened cytotoxic effects in sensitive cell lines, offering a potential strategy against treatment resistance in lung cancer. Additionally, co-culturing with macrophages has been found to induce alterations in gene expression profiles in lung cancer cell lines (2). Therefore, this study aimed to investigate changes in gene expressions associated with apoptosis in lung cancer cells when exposed to a combination of the proteasome inhibitor ixazomib, the HDAC inhibitor givinostat, and differentiated M1 macrophages.

Materials and Methods: The IC50 values of ixazomib and givinostat on A549 lung cancer cells were determined using the MTT method. A range of concentrations of these drugs (400, 100, 10, and 1 µM) were administered to A549 cells, and their viabilities were assessed after 24 hours. Following exposure to the determined IC50 concentrations for 24 hours, total RNA was isolated from A549 cells treated with ixazomib alone, ixazomib+givinostat, and THP-1 monocyte cells differentiated into M1 macrophages and co-cultured with this combination. Subsequently, RT-PCR experiments were conducted to assess alterations in apoptosis-related genes.

Results: Based on the results of the anti-proliferative effect analysis, the IC50 values for ixazomib and givinostat were determined to be 2.42 µM and 7.32 µM, respectively. According to the RT-PCR results, variations of up to 48.99-fold were observed in the NFKB2, NFKBIA, NFKBIB, RELB, IL-6, IL-8, TP53, PIK3CA, and BCR genes.

Conclusions: Significant alterations were particularly observed in genes involved in apoptosis-related pathways, especially in the presence of M1 macrophages. Additional investigation is warranted to thoroughly explore the heightened inflammatory response observed in lung cancer cells in the presence of these drugs.

References:

1. Denlinger CE et al. (2004). The Journal of Thoracic and Cardiovascular Surgery, 127(4):1078-1086.

2. Yuan A et al. (2015). Scientific Reports, 5(1), 14273.