Vitamin K2 Suppresses Cell Death Mediated By COVID-19 and Enhances the Activity of ABL Tyrosine Kinase Inhibitors Against Chronic Myeloid Leukemia Cells
Authors: Okabe Seiichi , Arai Yuya , Gotoh Akihiko 
Published: December 2024

Introduction:

The COVID-19 pandemic, driven by SARS-CoV-2, has significantly impacted global health. SARS-CoV-2 features an RNA genome and four structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). Despite the decline in severe COVID-19 cases, patients with hematological malignancies remain at a heightened risk for hospitalization. Hence, novel therapeutic strategies are essential for treating COVID-19 in patients with hematopoietic malignancies, including chronic myeloid leukemia (CML). Vitamin K, a fat-soluble vitamin, is vital for blood coagulation, bone health, antioxidative activities, and immune regulation. It exists primarily in two forms: VK1 (phylloquinone) and VK2 (menaquinone). VK2 is particularly significant for bone and cardiovascular health and may offer therapeutic benefits in this context.

Materials and Method:

The study investigated the potential of SARS-CoV-2 proteins to induce cell death in CML cells and examined if VK2 could inhibit this effect. Furthermore, it explored whether VK2 could enhance the efficacy of ABL tyrosine kinase inhibitors (TKIs) in treating CML cells, including those resistant to ABL TKI therapy.

Results:

Gene expression profiles from CML patients were analyzed using the Gene Expression Omnibus (GEO) database, with focus on biological processes related to immune response and SARS-CoV-2 signaling pathways. Gene Ontology (GO) analysis of the data from CML patients indicated that immune effector response and vascular development were significantly enriched biological processes (GSE100026). The SARS-CoV-2 signaling pathway (WP5115) played notable roles in these immune effector responses. In severe COVID-19 cases, there was a significant increase in the gene expression of IL-1a, IL-1b, and IL-6 compared to healthy controls (GSE227341). Due to the respiratory and immune-mediated effects of SARS-CoV-2 virus infection, the CML cell line K562 was treated with an exogenous addition of the SARS-CoV-2 E protein. Treatment of K562 cells with the SARS-CoV-2 E protein led to a dose-dependent decrease in cell proliferation, heightened cytotoxicity, and increased caspase 3/7 activity. Cell death in K562 cells began within two hours. The apoptotic cell count rose due to the SARS-CoV-2 E protein, while the S1 protein did not trigger similar effects, suggesting that the E protein primarily causes cytotoxicity in CML cells. VK2 treatment protected CML cells from the damage caused by the SARS-CoV-2 E protein. Our results showed that VK2 significantly reduced the levels of IL-1a, IL-1b, and IL-6. Additionally, VK2 suppressed the growth of both K562 and ponatinib-resistant K562 (K562 PR) cells in a dose-responsive manner, enhanced cytotoxicity, and diminished colony formation. When used with imatinib, VK2 further inhibited cell proliferation, raised caspase 3/7 activity, and led to increased cytotoxicity in both K562 and K562 PR cells, and diminished colony formation. Co-treatment also resulted in a significant reduction in mitochondrial membrane potentials (MMP), indicating impaired mitochondrial function and reduced cellular viability.

Conclusion:

The research shows that the SARS-CoV-2 E protein triggers cell death in CML cells, and VK2 effectively mitigates this harm. In addition, VK2 boosts the efficacy of imatinib against CML cells, even those resistant to ABL TKI therapy. These results indicate that VK2 may be a potential treatment option for CML patients, particularly during the COVID-19 pandemic, as it provides both protective and therapeutic advantages.