Research ArticleExperimental Studies
Open Access

Activity of Ponatinib and Vitamin K2 Against Myelodysplastic Syndrome and Acute Myeloid Leukemia Cells

SEIICHI OKABE, SEIICHIRO YOSHIZAWA, KAI OSONE, YUYA ARAI, MITSURU MORIYAMA and DAIGO AKAHANE
Anticancer Research March 2026, 46 (3) 1247-1257; DOI: https://doi.org/10.21873/anticanres.18026

Abstract

Background/Aim: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy often characterized by poor response to conventional therapies and frequent relapse. Ponatinib, a third-generation tyrosine kinase inhibitor, has demonstrated efficacy in various leukemias but remains underexplored in AML. Vitamin K2 (VK2), a fat-soluble vitamin, has recently been implicated in inducing apoptosis in leukemia cells. This study aimed to evaluate the therapeutic potential of ponatinib and VK2, alone and in combination, across five AML cell lines.

Materials and Methods: SKM-1 (myelodysplastic syndrome cell line) and AML cell lines MOLM-14, Kasumi-1, THP-1, and MV4-11 were tested. Cells were plated in 96-well plates and exposed to ponatinib or VK2, and cell viability and cytotoxicity were assessed. After 48 or 72 h of incubation, luminescence or absorbance was recorded, and cell numbers were quantified. Cells were plated in MethoCult medium supplemented with the indicated drug concentrations and incubated for 10 days at 37°C in a humidified 5% CO2 atmosphere. Colonies containing more than 50 cells were enumerated, and representative images were captured. Caspase-3/7 activity was measured after 48 h of drug exposure, and luminescence signals were detected. Cells were stained with the JC-1 MitoMP Detection Kit and analyzed using a fluorescence microplate reader. Mitochondrial membrane potential was determined by calculating the ratio of red to green fluorescence intensity. Intracellular adenosine triphosphate levels were quantified.

Results: Ponatinib exhibited cell line-dependent cytotoxic effects, with MOLM-14 and MV4-11 being the most sensitive. VK2 suppressed cell viability in all tested lines, with synergistic enhancement when combined with ponatinib. The combination treatment significantly increased apoptosis, reduced colony formation, and disrupted mitochondrial membrane potential.

Conclusion: The combined ponatinib and VK2 treatment synergistically impairs AML cell survival by enhancing apoptosis, suppressing clonogenic growth, and disrupting mitochondrial function. This dual targeting of oncogenic kinase signaling and metabolic integrity supports the ponatinib–VK2 combination as a promising therapeutic strategy for AML.

Keywords:

Introduction

Acute myeloid leukemia (AML) is a type of clonal blood cancer that interferes with normal blood cell production, eventually causing bone marrow failure and death (1). AML is a genetically complex, dynamic disease (1). Abnormal signaling of the FMS-like tyrosine kinase 3 (FLT3) receptor is prevalent in AML and significantly affects the biological understanding and clinical treatment of the disease (2). Individuals with AML who have FLT3 mutations often experience severe illness, face a higher likelihood of relapse following treatment, and generally have poorer clinical outcomes compared with those with wild type FLT3 (2). The frequency of these changes depends on the patient’s age, history of blood-related cancers, and previous treatment with chemotherapy and/or radiotherapy for any cancer type (1). Since 2010, molecular data have been integrated into AML prognostication, gradually leading to the inclusion of targeted therapies in the initial treatment strategy of induction chemotherapy and subsequent management (3). Even with the advent of targeted treatments and improvements in supportive care, the 5-year overall survival rate for adult AML remains under 30%, especially among older patients (4). Standard induction therapy, which generally includes regimens based on cytarabine and anthracycline, leads to complete remission in numerous patients. Nevertheless, most patients eventually experience a relapse due to the survival of leukemic stem cells and the emergence of drug resistance (5, 6). Therefore, developing new therapeutic strategies to address the proliferative and metabolic weaknesses of AML is essential.

Recent studies have concentrated on targeting the abnormal signaling pathways in leukemia cells (7). Receptor tyrosine kinases, such as FLT3, are a class of molecular targets that are frequently mutated or aberrantly activated in AML (8). Ponatinib is a third-generation, multi-targeted tyrosine kinase inhibitor (TKI) initially designed to suppress BCR::ABL1 activity, including the resistant T315I gatekeeper mutation (9). In addition to its use in treating chronic myeloid leukemia (CML), ponatinib also targets the kinases FLT3, fibroblast growth factor receptor, c-KIT, and platelet-derived growth factor receptor, which play a role in the pathophysiology of AML (10). Earlier research has shown that ponatinib can effectively inhibit AML cells with FLT3-Internal Tandem Duplication (ITD) positivity (11). However, its overall role in AML and its potential when used in combination therapies remain unclear.

Vitamin K (VK) refers to a group of fat-soluble vitamins, each serving as a cofactor for the γ-carboxylase enzyme (12). VK is a crucial bioactive substance necessary for optimal body function. It exists in different forms, primarily as phylloquinone (VK1) and menaquinones (VK2), characterized by two main structural types (13). The structural differences between VK1 and VK2 result in variations in their absorption rates, tissue distribution, and bioavailability (13). VK2 is involved in blood clotting, calcium balance, and mitochondrial function (14). This vitamin triggers apoptosis in blood cancers, such as acute leukemia (15).

Therefore, we hypothesized that dual targeting with ponatinib and VK2 might enhance anti-leukemic efficacy by integrating kinase inhibition with mitochondrial disruption. This research explored the therapeutic effects of ponatinib and VK2, individually and in combination, across various AML cell lines with different genetic profiles. To understand the functional outcomes of this drug combination, we evaluated cell viability, cytotoxic effects, caspase activation, mitochondrial membrane potential, adenosine triphosphate (ATP) levels, and colony formation. Our findings provide new insights into a promising combinatorial strategy for AML treatment that targets survival signaling and metabolic integrity.

Materials and Methods

Cell lines and reagents. SKM-1 (myelodysplastic syndrome [MDS] cell line, FLT3 wild type), MOLM-14 (AML cell line, FLT3-ITD mutation), and Kasumi-1 (AML cell line, c-KIT mutation) were obtained from the Japanese Collection of Research Bioresources Cell Bank (Ibaraki, Osaka, Japan). THP-1 (FLT3 wild type) and MV4-11 (FLT3-ITD mutation) AML cell lines were purchased from the American Type Culture Collection (Manassas, VA, USA). All MDS and AML cell lines were maintained in RPMI1640 medium supplemented with 10% fetal bovine serum and 1% penicillin–streptomycin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA). Ponatinib was obtained from MedKoo Biosciences (Morrisville, NC, USA), and VK2 (menaquinone-4; MK-4) was purchased from Eisai Co., Ltd. (Tokyo, Japan). Ponatinib was dissolved in dimethyl sulfoxide to prepare stock solutions, while VK2 was diluted directly in the culture medium before use. All other reagents were procured from Merck KGaA (Darmstadt, Germany).

Cell viability and cytotoxicity assays. Cells were plated in 96-well plates and exposed to serial dilutions of ponatinib or VK2. Cell viability was determined using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, WI, USA), the Cell Counting Kit-8 (Dojindo Molecular Technologies, Kumamoto, Japan), or by trypan blue exclusion (0.4% w/v). Cytotoxicity was assessed by measuring lactate dehydrogenase (LDH) release with the LDH Cytotoxicity Assay Kit (Dojindo Molecular Technologies). Following 48 or 72 h of incubation, luminescence or absorbance at 450 or 490 nm was recorded using a NIVO multimode plate reader (Revvity, Waltham, MA, USA). Cell numbers were also quantified using a TC10 Automated Cell Counter (Bio-Rad, Hercules, CA, USA). All experiments were performed in triplicate.

Colony formation assay. Kasumi-1 cells were maintained in MethoCult™ medium (Catalog #04437; STEMCELL Technologies, Vancouver, BC, Canada), a methylcellulose-based culture medium, according to the manufacturer’s protocol. In brief, 5 × 102 cells were plated in MethoCult medium supplemented with the indicated drug concentrations and incubated for 10 days at 37°C in a humidified 5% CO2 atmosphere. Colonies containing more than 50 cells were enumerated, and representative images were captured using an EVOS FL Digital Inverted Fluorescence Microscope (Thermo Fisher Scientific, Waltham, MA, USA).

Caspase-3/7 activity. Caspase-3/7 activity was measured after 48 h of drug exposure using the Caspase-Glo® 3/7 Assay (Promega) according to the manufacturer’s instructions. Luminescence signals were detected with a Nivo multimode plate reader.

Mitochondrial Membrane Potential (ΔΨm). Cells were stained with the JC-1 MitoMP Detection Kit (Dojindo Molecular Technologies) and analyzed using a fluorescence microplate reader. Mitochondrial membrane potential (ΔΨm) was determined by calculating the ratio of red to green fluorescence intensity.

Intracellular ATP measurement. Intracellular ATP levels were quantified using the Intracellular ATP Assay Kit Ver. 2 (Toyo B-Net Co., Ltd., Tokyo, Japan) according to the manufacturer’s instructions. Luminescent signals were measured with a Revvity Nivo multimode plate reader.

Statistical analysis. Data are presented as the mean ± standard deviation from at least three independent experiments. Statistical analyses were conducted using one-way or two-way analysis of variance, followed by Tukey’s post hoc test. Statistical significance was defined as p<0.05.

Results

Ponatinib exhibits variable cytotoxicity across AML cell lines. To assess the anti-leukemic effects of ponatinib, we treated five AML or MDS cell lines (SKM-1, MOLM-14, Kasumi-1, THP-1, and MV4-11) with increasing concentrations of the drug. The dose response analysis indicated a significant reduction in cell viability induced by ponatinib in MOLM-14, Kasumi-1, and MV4-11 cells, while SKM-1 and THP-1 cells showed relative resistance (Figure 1A). Consistently, cytotoxicity assays demonstrated dose-dependent effects of ponatinib on MOLM-14 cells but not on SKM-1 cells (Figure 1B). Similarly, Kasumi-1 and MV4-11 cells exhibited increased cytotoxicity in response to ponatinib, whereas THP-1 cells did not show a significant increase (Figure 1C).

Figure 1.
Figure 1.

Responses of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells to ponatinib. (A) MDS cell line (SKM-1) and AML cell lines (MOLM-14, Kasumi-1, THP-1, and MV4-11) were treated with ponatinib (0 nM–1 μM) for 72 h. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. (B) SKM-1 and MOLM-14 cells were treated with ponatinib (0 nM–1 μM) for 48 h. The cytotoxicity was analyzed using a Cytotoxicity LDH Assay Kit. Data were normalized to untreated controls and are presented as means±standard deviations. ****p<0.0001, compared with the control. Ns: not significant. (C) Kasumi-1, THP-1, and MV4-11 cells were treated with ponatinib (0 nM–1 μM) for 48 h. The cytotoxicity was analyzed using a Cytotoxicity LDH Assay Kit. Data were normalized to untreated controls and are presented as means ± standard deviations. **** <0.0001, compared with the control. ns: not significant.

Kasumi-1 cells are selectively sensitive to imatinib. Imatinib is a TKI that is a relatively specific ATP-binding site antagonist of BCR::ABL1, PDGF receptor, and c-Kit (16). Imatinib sensitivity was profiled across AML cell lines using viability and cytotoxicity assays. Only Kasumi-1 showed a significant, dose-dependent decline in viability (Figure 2A) with a concordant increase in cytotoxicity (Figure 2B), whereas MOLM-14 and MV4-11 remained refractory across the tested concentrations. These data indicate that imatinib responsiveness in AML is not uniform but restricted to Kasumi-1, implicating line-specific molecular determinants of drug sensitivity.

Figure 2.
Figure 2.

Responses of acute myeloid leukemia (AML) cells to imatinib. (A) AML cell lines (Kasumi-1, MOLM-14, and MV4-11) were treated with imatinib (0 nM–10 μM) for 72 h. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. (B) AML cell lines (Kasumi-1, MOLM-14, and MV4-11) were treated with imatinib (0 nM-1 μM) for 48 h. The cytotoxicity was analyzed using a Cytotoxicity LDH Assay Kit. Data were normalized to untreated controls and are presented as means±standard deviations. ****p<0.0001, compared with the control. ns: not significant.

VK2 suppresses viability and induces cytotoxicity in AML cells. Vitamin K exhibits not only coagulation-related activity but also possesses anti-inflammatory, antioxidant, and anticancer properties (17). We tested VK2 against a panel of MDS and AML cell lines to assess its efficacy. The cell lines were treated with varying concentrations of VK2 for 72 h, and cell viability was measured using standard assays. VK2 treatment led to a concentration-dependent decrease in cell viability across all five AML cell lines, with MOLM-14 and MV4-11 showing the highest sensitivity (Figure 3A). Cytotoxicity assays revealed significant VK2-induced cytotoxicity in MOLM-14, MV4-11, and THP-1 cells (Figure 3B and C), while SKM-1 and Kasumi-1 cells demonstrated relatively modest responses.

Figure 3.
Figure 3.

Effects of vitamin K2 (VK2) on myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells. (A) MDS cell line (SKM-1) and AML cell lines (MOLM-14, Kasumi-1, THP-1, and MV4-11) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) with the indicated concentrations (0 nM-50 μM) of VK2 for 72 h. Cell growth was evaluated using the CellTiter-Glo™ Luminescent Cell Viability Assay Kit or trypan blue exclusion (0.4% w/v). (B) SKM-1 and MOLM-14 cells were treated with VK2 (0 nM-50 μM) for 48 h. The cytotoxicity was analyzed using a Cytotoxicity LDH Assay Kit. Data were normalized to untreated controls and are presented as means ± standard deviations. ****p<0.0001, compared with the control. ns: not significant. (C) Kasumi-1, THP-1, and MV4-11 cells were treated with VK2 (0 nM–50 μM) for 48 h. The cytotoxicity was analyzed using a Cytotoxicity LDH Assay Kit. Data were normalized to untreated controls and are presented as means ± standard deviations. ****p<0.0001, compared with the control.

Combined effects of ponatinib and VK2 on AML cell viability, cytotoxicity, and apoptosis. We next investigated the combined effects of ponatinib and VK2. The combined treatment with ponatinib and VK2 significantly reduced cell viability in MOLM-14 cells compared with either agent alone, while SKM-1 cells showed minimal sensitivity (Figure 4A). In Kasumi-1, THP-1, and MV4-11 cells, the combination led to a notable decrease in viability, with the most substantial reduction observed in MV4-11 cells (Figure 4B). Cytotoxicity assays indicated a marked increase in cell death in MOLM-14 cells with the combination, whereas SKM-1 cells remained largely unaffected (Figure 4C). In Kasumi-1, THP-1, and MV4-11 cells, the combination significantly enhanced cytotoxicity, particularly in MV4-11 (Figure 4D). Caspase-3/7 activity was substantially elevated in MOLM-14, Kasumi-1, and MV4-11 cells following the combined treatment, surpassing the effect of either drug alone. In contrast, SKM-1 and THP-1 cells exhibited minimal caspase activation (Figure 4E and 4F). These findings suggest that ponatinib and VK2 exert synergistic anti-leukemic effects in select AML cell lines, characterized by reduced viability, increased cytotoxicity, and enhanced apoptotic signaling, with MOLM-14 and MV4-11 showing the highest sensitivity.

Figure 4.
Figure 4.
Figure 4.

Co-treatment with ponatinib and vitamin K2 (VK2) enhances antileukemic activity across myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells. MDS cell line (SKM-1) and AML cell lines (MOLM-14, Kasumi-1, THP-1, and MV4-11) were incubated with 10 nM ponatinib and/or 10 μM VK2 for 48 or 72 h. Cell viability (A, B), cytotoxicity (C, D), and caspase-3/7 activity (E, F) were evaluated. *p<0.05, **p<0.01, ***p<0.001,****p<0.0001, vs. the control sample. ns: Not significant.

Effects of ponatinib and VK2 on colony formation, mitochondrial membrane potential, and ATP levels in AML cells. We next performed a colony formation assay to further evaluate the long-term proliferative capacity of the cells. Consistent with the observed reduction in cell viability, colony formation assays in Kasumi-1 cells showed that combined treatment with ponatinib and VK2 markedly decreased the number of colonies compared with either drug alone (Figure 5A). Representative images further confirmed a notable decrease in the number and size of colonies following the combination treatment. Analysis of mitochondrial membrane potential (ΔΨm) showed a significant reduction in MOLM-14 cells treated with ponatinib and VK2 compared with monotherapy, while SKM-1 cells exhibited minimal change (Figure 5B). Similarly, Kasumi-1 and MV4-11 cells experienced substantial ΔΨm loss in response to the combination, whereas THP-1 cells remained largely unaffected (Figure 5C). Combination treatment markedly reduced intracellular ATP levels in MV4-11 cells compared with single agents, and a comparable decrease was also observed in Kasumi-1 cells (Figure 5D). These results indicate that ponatinib and VK2 act synergistically to suppress leukemic cell growth and metabolic activity.

Figure 5.
Figure 5.
Figure 5.

Combined bortezomib and panobinostat treatment suppresses colony formation, disrupts mitochondrial membrane potential, and induces apoptosis. (A) Kasumi-1 cells were treated with 10 nM ponatinib, with or without 10 μM vitamin K2 (VK2), for 7–9 days. The colonies per dish were photographed using a digital camera and counted using an EVOS FL digital inverted fluorescence microscope. The quantification graph shows colony formation and representative images from three independent sets of experiments (scale bar: 1,000 μm). Results are representative of three independent experiments. Significance is expressed as ****p<0.0001 vs. the control. (B, C) MDS cell line (SKM-1) and AML cell lines (MOLM-14, Kasumi-1, THP-1, and MV4-11) were treated with 10 nM ponatinib with or without 10 μM VK2 for 48 h. MMP was analyzed using a mitochondrial staining kit. Significance is expressed as ***p <0.001, ****p <0.0001 vs. the control. (D) Kasumi-1 and MV4-11 cells were treated with 10 nM ponatinib with or without 10 μM VK2 for 48 h. Intracellular adenosine triphosphate (ATP) levels were determined using the “Cell” ATP Assay Reagent Ver. 2 Kit. ****p <0.0001 vs. the control.

Discussion

In this study, we investigated the anti-leukemic activity of the TKI ponatinib and the lipophilic compound VK2 in AML and MDS cell lines, with particular emphasis on their individual and synergistic effects. Ponatinib exerted marked anti-proliferative and cytotoxic effects in a subset of AML cell lines, particularly MOLM-14, Kasumi-1, and MV4-11, whereas SKM-1 and THP-1 exhibited relative resistance. These differential responses likely reflect the diversity of molecular backgrounds, including dependence on specific signaling pathways such as FLT3 or c-kit. By contrast, imatinib demonstrated activity only in Kasumi-1 cells, possibly because of c-KIT mutation-driven sensitivity, underscoring the heterogeneity of kinase inhibitor responsiveness in AML.

VK2 treatment led to a concentration-dependent reduction in cell viability in all five AML cell lines, with MV4-11 being the most sensitive. This broad yet variable activity profile is consistent with pleiotropic mechanisms. The production of reactive oxygen species induced by VK2 was observed to precede the activation of apoptotic signaling pathways (18). The pronounced sensitivity observed in MV4-11 suggests that AML subtypes with high metabolic dependency or mitochondrial vulnerability are particularly susceptible to VK2.

In an earlier phase 1 trial of ponatinib, the overall response rate (indicating partial remission or better) among patients with AML was 25% (three of 12 patients) (19). Furthermore, two patients reached complete remission but with incomplete recovery of blood counts, while another patient achieved partial remission in FLT-ITD AML cases (19). Ponatinib was generally well tolerated in this limited cohort of patients with AML, exhibiting a safety profile comparable to that observed in CML. Therefore, these findings underscore the potential of ponatinib as a therapeutic candidate for patients with FLT3-ITD–mutated AML and other hematologic malignancies driven by aberrant c-KIT signaling (11).

The combination of ponatinib and VK2 produced synergistic anti-leukemic effects that exceeded those of either agent alone. This was most evident in MOLM-14 and MV4-11 cells, where combination treatment significantly reduced viability, enhanced cytotoxicity, and markedly increased caspase-3/7 activation. The interaction may result from complementary mechanisms: ponatinib-mediated inhibition of oncogenic kinase signaling (including c-kit and FLT3 pathways) and VK2-induced mitochondrial and metabolic stress. By converging on proliferative and survival pathways, the combination appears to amplify apoptotic signaling, resulting in more profound cell death.

Mechanistically, the combination treatment was associated with substantial impairment of mitochondrial function, as evidenced by loss of mitochondrial membrane potential (ΔΨm) in MOLM-14, Kasumi-1, and MV4-11 cells. Furthermore, intracellular ATP levels were significantly depleted, particularly in MV4-11 cells, suggesting that energy metabolism collapse is a critical driver of apoptosis in this context. Colony formation assays further confirmed that the combination suppressed long-term clonogenic capacity in Kasumi-1 cells, providing functional evidence that the treatment disrupts the self-renewal potential of leukemic cells.

The combination of decitabine, venetoclax, and ponatinib is safe and effective in patients with advanced-stage CML, even for those who have undergone multiple prior treatments or possess high-risk disease characteristics (20). In a previous phase II trial, ponatinib administration following allogeneic hematopoietic stem cell transplantation, despite a favorable toxicity profile, did not reduce relapse or improve survival rates among this small group of patients with AML and FLT3-ITD mutations (21).

We previously demonstrated that the combination of the WEE1 inhibitor MK-1775 and VK2 synergistically enhanced apoptosis and reduced clonogenicity in parental and TKI-resistant CML cells (22). Similar mechanisms may underlie the improved anti-leukemic activity observed in AML models.

Our findings support the concept that dual targeting of oncogenic signaling and mitochondrial metabolism represents a promising strategy for AML therapy. Ponatinib, with its broad kinase inhibition profile, may sensitize cells to metabolic stress induced by VK2, thereby overcoming resistance mechanisms that limit the efficacy of kinase inhibitors alone. Given the relative resistance of SKM-1 and THP-1 cells to one or both agents, further investigation is warranted to define the molecular determinants of sensitivity, such as mutational status, metabolic phenotype, and mitochondrial dependency.

Conclusion

Ponatinib and VK2 synergistically reduce viability, induce apoptosis, and suppress clonogenic and metabolic activity in AML cells through combined inhibition of kinase signaling and mitochondrial disruption. These findings support the therapeutic potential of ponatinib–VK2 combination therapy for AML with kinase-driven and metabolic vulnerabilities.

Footnotes

  • Authors’ Contributions

    Seiichi Okabe: conceptualization (equal), investigation (equal), methodology (equal), writing – original draft (lead). Seiichiro Yoshizawa: conceptualization (equal), investigation (equal). Kai Osone: conceptualization (equal), investigation (equal). Yuya Arai: conceptualization (equal), investigation (equal). Mitsuru Moriyama: methodology (equal), investigation (equal). Daigo Akahane: project administration (supporting), supervision (equal), writing – review and editing (equal).

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Funding

    None.

  • Received December 24, 2025.
  • Revision received January 21, 2026.
  • Accepted January 22, 2026.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

References

  1. ↵
    1. Venugopal S,
    2. Sekeres MA
    : Contemporary management of acute myeloid leukemia: a review. JAMA Oncol 10(10): 1417, 2024. DOI: 10.1001/jamaoncol.2024.2662
    OpenUrlCrossRefPubMed
  2. ↵
    1. Ambinder AJ,
    2. Levis M
    : Potential targeting of FLT3 acute myeloid leukemia. Haematologica 106(3): 671-681, 2021. DOI: 10.3324/haematol.2019.240754
    OpenUrlCrossRefPubMed
  3. ↵
    1. Kantarjian HM,
    2. DiNardo CD,
    3. Kadia TM,
    4. Daver NG,
    5. Altman JK,
    6. Stein EM,
    7. Jabbour E,
    8. Schiffer CA,
    9. Lang A,
    10. Ravandi F
    : Acute myeloid leukemia management and research in 2025. CA Cancer J Clin 75(1): 46-67, 2025. DOI: 10.3322/caac.21873
    OpenUrlCrossRefPubMed
  4. ↵
    1. Lai C,
    2. Doucette K,
    3. Norsworthy K
    : Recent drug approvals for acute myeloid leukemia. J Hematol Oncol 12(1): 100, 2019. DOI: 10.1186/s13045-019-0774-x
    OpenUrlCrossRefPubMed
  5. ↵
    1. Yavuz S,
    2. Malkan UY
    : Comparison of regimens targeting complete remission in the first-line treatment of acute myeloid leukemia patients. Eur Rev Med Pharmacol Sci 28(21): 4493–4506, 2024. DOI: 10.26355/eurrev_202411_36908
    OpenUrlCrossRefPubMed
  6. ↵
    1. Takao S,
    2. Morell V,
    3. Uni M,
    4. Slavit A,
    5. Rha S,
    6. Cheng S,
    7. Schmalbrock LK,
    8. Brown FC,
    9. Beneyto-Calabuig S,
    10. Koche RP,
    11. Velten L,
    12. Kentsis A
    : Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance. Nat Commun 16(1): 3196, 2025. DOI: 10.1038/s41467-025-58370-9
    OpenUrlCrossRefPubMed
  7. ↵
    1. Hansen Q,
    2. Bachas C,
    3. Smit L,
    4. Cloos J
    : Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication. Cancer Drug Resist 5(2): 344-367, 2022. DOI: 10.20517/cdr.2021.140
    OpenUrlCrossRefPubMed
  8. ↵
    1. Fernandez S,
    2. Desplat V,
    3. Villacreces A,
    4. Guitart AV,
    5. Milpied N,
    6. Pigneux A,
    7. Vigon I,
    8. Pasquet JM,
    9. Dumas PY
    : Targeting tyrosine kinases in acute myeloid leukemia: why, who and how? Int J Mol Sci 20(14): 3429, 2019. DOI: 10.3390/ijms20143429
    OpenUrlCrossRef
  9. ↵
    1. Senapati J,
    2. Sasaki K,
    3. Issa GC,
    4. Lipton JH,
    5. Radich JP,
    6. Jabbour E,
    7. Kantarjian HM
    : Management of chronic myeloid leukemia in 2023 - common ground and common sense. Blood Cancer J 13(1): 58, 2023. DOI: 10.1038/s41408-023-00823-9
    OpenUrlCrossRefPubMed
  10. ↵
    1. Tan FH,
    2. Putoczki TL,
    3. Stylli SS,
    4. Luwor RB
    : Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies. Onco Targets Ther 12: 635-645, 2019. DOI: 10.2147/OTT.S189391
    OpenUrlCrossRefPubMed
  11. ↵
    1. Gozgit JM,
    2. Wong MJ,
    3. Wardwell S,
    4. Tyner JW,
    5. Loriaux MM,
    6. Mohemmad QK,
    7. Narasimhan NI,
    8. Shakespeare WC,
    9. Wang F,
    10. Druker BJ,
    11. Clackson T,
    12. Rivera VM
    : Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther 10(6): 1028-1035, 2011. DOI: 10.1158/1535-7163.MCT-10-1044
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Shea MK,
    2. Booth SL
    : Vitamin K. Adv Nutr 13(1): 350-351, 2022. DOI: 10.1093/advances/nmab133
    OpenUrlCrossRefPubMed
  13. ↵
    1. Halder M,
    2. Petsophonsakul P,
    3. Akbulut AC,
    4. Pavlic A,
    5. Bohan F,
    6. Anderson E,
    7. Maresz K,
    8. Kramann R,
    9. Schurgers L
    : Vitamin K: Double bonds beyond coagulation insights into differences between vitamin K1 and K2 in health and disease. Int J Mol Sci 20(4): 896, 2019. DOI: 10.3390/ijms20040896
    OpenUrlCrossRefPubMed
  14. ↵
    1. Zhang T,
    2. O’Connor C,
    3. Sheridan H,
    4. Barlow JW
    : Vitamin K2 in health and disease: a clinical perspective. Foods 13(11): 1646, 2024. DOI: 10.3390/foods13111646
    OpenUrlCrossRefPubMed
  15. ↵
    1. Yaguchi M,
    2. Miyazawa K,
    3. Katagiri T,
    4. Nishimaki J,
    5. Kizaki M,
    6. Tohyama K,
    7. Toyama K
    : Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance the effect of all-trans retinoic acid. Leukemia 11(6): 779-787, 1997. DOI: 10.1038/sj.leu.2400667
    OpenUrlCrossRefPubMed
  16. ↵
    1. Li W,
    2. Croce K,
    3. Steensma DP,
    4. McDermott DF,
    5. Ben-Yehuda O,
    6. Moslehi J
    : Vascular and metabolic implications of novel targeted cancer therapies. J Am Coll Cardiol 66(10): 1160-1178, 2015. DOI: 10.1016/j.jacc.2015.07.025
    OpenUrlFREE Full Text
  17. ↵
    1. Chen A,
    2. Li J,
    3. Shen N,
    4. Huang H,
    5. Hang Q
    : Vitamin K: New insights related to senescence and cancer metastasis. Biochim Biophys Acta Rev Cancer 1879(2): 189057, 2024. DOI: 10.1016/j.bbcan.2023.189057
    OpenUrlCrossRef
  18. ↵
    1. Xv F,
    2. Chen J,
    3. Duan L,
    4. Li S
    : Research progress on the anticancer effects of vitamin K2. Oncol Lett 15(6): 8926-8934, 2018. DOI: 10.3892/ol.2018.8502
    OpenUrlCrossRefPubMed
  19. ↵
    1. Shah NP,
    2. Talpaz M,
    3. Deininger MW,
    4. Mauro MJ,
    5. Flinn IW,
    6. Bixby D,
    7. Lustgarten S,
    8. Gozgit JM,
    9. Clackson T,
    10. Turner CD,
    11. Haluska FG,
    12. Kantarjian H,
    13. Cortes JE
    : Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol 162(4): 548-552, 2013. DOI: 10.1111/bjh.12382
    OpenUrlCrossRefPubMed
  20. ↵
    1. Short NJ,
    2. Nguyen D,
    3. Jabbour E,
    4. Senapati J,
    5. Zeng Z,
    6. Issa GC,
    7. Abbas H,
    8. Nasnas C,
    9. Qiao W,
    10. Huang X,
    11. Borthakur G,
    12. Chien K,
    13. Haddad FG,
    14. Pemmaraju N,
    15. Karrar OS,
    16. Nguyen D,
    17. Konopleva M,
    18. Kantarjian H,
    19. Ravandi F
    : Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial. Lancet Haematol 11(11): e839-e849, 2024. DOI: 10.1016/S2352-3026(24)00250-3
    OpenUrlCrossRef
  21. ↵
    1. Chevallier P,
    2. Thiebaut A,
    3. François S,
    4. Chantepie S,
    5. Rubio MT,
    6. Labussiere-Wallet H,
    7. Brissot E,
    8. Maillard N,
    9. Huynh A,
    10. Coiteux V,
    11. Jullien M,
    12. Garnier A,
    13. Le Bourgeois A,
    14. Peterlin P,
    15. Guillaume T
    : A phase II study of ponatinib for prevention of relapse after allogeneic transplantation in FLT3 internal tandem duplication mutation-positive (FLT3(−)ITD(+)) acute myeloid leukemia: the PONALLO trial. Haematologica 110(10): 2525-2529, 2025. DOI: 10.3324/haematol.2025.287681
    OpenUrlCrossRefPubMed
  22. ↵
    1. Okabe S,
    2. Arai Y,
    3. Gotoh A,
    4. Akahane D
    : Combination of WEE1 inhibitor and vitamin K2 enhances therapeutic efficacy in chronic myeloid leukemia. Cancer Innov 4(5): e70024, 2025. DOI: 10.1002/cai2.70024
    OpenUrlCrossRef
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Activity of Ponatinib and Vitamin K2 Against Myelodysplastic Syndrome and Acute Myeloid Leukemia Cells
SEIICHI OKABE, SEIICHIRO YOSHIZAWA, KAI OSONE, YUYA ARAI, MITSURU MORIYAMA, DAIGO AKAHANE
Anticancer Research Mar 2026, 46 (3) 1247-1257; DOI: 10.21873/anticanres.18026
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