Prolonged Β-Hydroxybutyrate-Mediated Ketosis Enhances Ponatinib Response of K562 Chronic Myeloid Leukaemia Cells

Abstract

Prolonged Β-Hydroxybutyrate-Mediated Ketosis Enhances Ponatinib Response of K562 Chronic Myeloid Leukaemia Cells

Abstract

Purpose: Ketosis is a metabolic state characterized by production of ketone bodies, including acetoacetate, β-hydroxybutyrate (BHB), and acetone, in response to reduced blood glucose levels. BHB stands out as the principal ketone body in nutritional ketosis which has diverse therapeutic implications for metabolic, nondegenerative and neoplastic disorders. In current study we investigated the impact of ketosis on chronic myeloid leukaemia (CML) cell viability and drug response. Materials and Methods: We investigated the impact of BHB-mediated ketosis on the viability of K562 cells, an in vitro model of CML, and explored the influence of BHB on the sensitivity of these cells to ponatinib, a multi-targeted tyrosine kinase inhibitor used in CML treatment. We used MTT assay to measure cell viability and Hoechst/PI assay to measure cell death. Results: Our findings reveal that BHB concentrations ranging from 1 mM to 5 mM, which fall within the physiological range of ketosis, elicit a minimal yet concentration-dependent reduction in cell viability. We also observed that while a 24-hour pre-treatment with BHB did not enhance the response of K562 cells to ponatinib, prolonged ketosis (4 days) improved response of cells to the drug by decreasing final cell viability from 25.15% to 13.12%. The primary mode of viability inhibition by ponatinib was cell death which was further intensified by exposure to prolonged ketosis. Conclusion: Ketosis induced by ketogenic diet of ketone body supplementation is considered as safe and effective adjuvant cancer therapy options and here, we report its potential effectiveness in the context of CML.

Keywords

• ketosis
• β-hydroxybutyrate
• cancer
• chronic myeloid leukaemia
• ketogenic diet

References

1. Cahill GF. Fuel Metabolism in Starvation. Annu Rev Nutr 2006;26(1):1–22.
2. Newman JC, Verdin E. β-Hydroxybutyrate: A Signaling Metabolite. Annual Review of Nutrition 2017;37(1):51–76.
3. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, Leukotrienes and Essential Fatty Acids 2004;70(3):309–19.
4. Paoli A, Bosco G, Camporesi EM, Mangar D. Ketosis, ketogenic diet and food intake control: a complex relationship. Frontiers in Psychology 2015;6:27.
5. Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B. Ketogenic diet in the treatment of cancer - Where do we stand? Mol Metab 2020;33:102–21.
6. Römer M, Dörfler J, Huebner J. The use of ketogenic diets in cancer patients: a systematic review. Clin Exp Med 2021;21(4):501–36.
7. Neha, Chaudhary R. Ketogenic diet as a treatment and prevention strategy for cancer: A therapeutic alternative. Nutrition 2024;124:112427.
8. Tan FH, Putoczki TL, Stylli SS, Luwor RB. Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies. Onco Targets Ther 2019;12:635–45.

9. Tapani E, Taavitsainen M, Lindros K, Vehmas T, Lehtonen E. Toxicity of Ethanol in Low Concentrations. Acta Radiologica 1996;37(6):923–6.
10. Zhao H, Jin H, Xian J, Zhang Z, Shi J, Bai X. Effect of Ketogenic Diets on Body Composition and Metabolic Parameters of Cancer Patients: A Systematic Review and Meta-Analysis. Nutrients 2022;14(19):4192.
11. Plotti F, Terranova C, Luvero D, Bartolone M, Messina G, Feole L, et al. Diet and Chemotherapy: The Effects of Fasting and Ketogenic Diet on Cancer Treatment. Chemotherapy 2020;65(3–4):77–84.
12. Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 2018;560(7719):499–503.
13. Massaro F, Molica M, Breccia M. Ponatinib: A Review of Efficacy and Safety. Current Cancer Drug Targets 2018;18(9):847–56.
14. Moslehi JJ, Deininger M. Tyrosine Kinase Inhibitor–Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia. J Clin Oncol 2015;33(35):4210–8.
15. Mauro MJ, Cortes JE, Hochhaus A, Baccarani M, Hughes TP, Guilhot F, et al. Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials. Blood 2014;124(21):4552.
16. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr 2013;67(8):789–96.