Co-inhibition of MPS-1 with BCL-2 family inhibitors enhances lung cancer cell killing in 2D and 3D culture systems
DOI:
https://doi.org/10.48797/sl.2023.24Keywords:
PosterAbstract
Background: Lung cancer is the leading cause of cancer death worldwide, posing a significant public health challenge [1]. Currently available therapies, when administered as monotherapy, have limited efficacy, high toxicity, and can lead to increased tumor resistance. Overexpression of MPS-1, a protein kinase involved in mitosis, has been observed in various types of tumors. Its inhibition is associated with aberrant chromosome segregation, leading to cell death. Also, overexpression of anti-apoptotic proteins from the BCL-2 family has been reported in different cancer types, and inhibiting them can enhance cancer cell killing [2,3]; Objective: To assess the antitumor potential of combining a MPS-1 inhibitor with a BCL- 2 family inhibitor, in both 2D and 3D lung cancer cells (A549); Methods: MPS-1 mRNA and protein levels were assessed by qRT-PCR and western blot, respectively. In 2D cultures, the compounds cytotoxic activity was evaluated by MTT assay. The effects of the combination (antagonistic/additive/synergistic effects) were determined using the Combenefit software. The cell death was evaluated by TUNEL method and by flow cytometry (annexin V/propidium iodide). To assess the antiproliferative activity, the colony formation assay was performed. In 3D cultures, spheroid viability and apoptosis were determined by CellTiter-Glo assay and annexin V/ propidium iodide labeling, respectively; Results: Our results demonstrated that MPS-1 mRNA and protein levels were increased in A549 cells. Co-treatment of 2D cultures with the MPS-1 inhibitor and the BCL- 2 family inhibitor resulted in various synergistic points. The combination with the lowest pharmacological concentrations inhibited cancer cell proliferation, and induced cell death by apoptosis. The results were confirmed in a 3D spheroid model. Conclusions: Cancer cell killing activity of the MPS-1 inhibitor is enhanced when combined with the BCL- 2 family inhibitor, both in 2D and 3D cultures.
References
1. Duma, N.; Santana-Davila, R.; Molina, J. R., Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clinic proceedings 2019, 94 (8), 1623-1640.
2. Henriques, A. C.; Ribeiro, D.; Pedrosa, J.; Sarmento, B.; Silva, P. M. A.; Bousbaa, H., Mitosis inhibitors in anticancer therapy: When blocking the exit becomes a solution. Cancer letters 2019, 440-441, 64-81.
3. Pinto, B.; Novais, P.; Henriques, A. C.; Carvalho-Tavares, J.; Silva, P. M. A.; Bousbaa, H., Navitoclax Enhances the Therapeutic Effects of PLK1 Targeting on Lung Cancer Cells in 2D and 3D Culture Systems. Pharmaceutics 2022, 14 (6).
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Copyright (c) 2023 B. Pinto, P. Silva, B. Sarmento, J. Carvalho-Tavares, Hassan Bousbaa
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