menaquinone-6 and Myelodysplastic-Syndromes

Myelodysplastic syndrome is a hematopoietic stem cell disorder characterized by ineffective hematopoiesis and leukemic progression. Accumulation of various kinds of genetic alterations in oncogene and tumor suppressor gene develops and accelerates the disease. Recently, alpha-catenin gene has been identified as a candidate gene in the 5q- anomaly. Diagnostic criteria have been updated by Valent et al. WHO classification has become popular and WHO classification-based prognostic scoring system will be employed to evaluate prognosis. In our country, clinical studies on vitamin K2+D3 and cyclosporine A were conducted in low-risk patients, and their efficacy and safety have been reported. In US, molecular-targeting therapy with lenalidomide or demethylase is approved by FDA.

Topics: alpha Catenin; Antineoplastic Agents; Azacitidine; Cholecalciferol; Cyclosporine; Decitabine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lenalidomide; Myelodysplastic Syndromes; Prognosis; Thalidomide; Vitamin K 2; World Health Organization

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Evidence-Based Medicine; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Prognosis; Vitamin K 2

We performed an open-labeled single-arm prospective phase II clinical trial of vitamin K(2) (menatetrenone: VK2) monotherapy and VK2 plus 1alpha-hydroxyvitamin D(3) (alfacalcidol: VD3) combination therapy for myelodysplastic syndromes (MDS) with refractory anemia and refractory cytopenia with multilineage dysplasia, having either low or intermediate-1 risks of the IPSS. The overall response rate to VK2 monotherapy (45mg/day) after 16 weeks was 13% (5/38) including 4 cases with improvement of both anemia and thrombocytopenia and 1 case with thrombocytopenia. We then enrolled and evaluated 20 out of 33 VK2-monotherapy non-responders for VK2 plus VD3 (0.75microg/day) combination therapy. The overall response rate at 16 weeks after initiation of VK2 plus VD3 was 30% (6/20). HI for hemoglobin (Hb) was observed in 6 out of 11 patients (55%) and for thrombocytopenia in 3 out of 11 patients (27%), respectively. No HI was observed for neutropenia in VK2 monotherapy and VK2 plus VD3 combination therapy. It was suggested that IPSS scores and absolute neutrophil counts positively correlated, and Hb levels inversely correlated with the response to VK2 plus VD3 combination therapy. Our study demonstrated that VK2 plus VD3 combination therapy appears to be promising for improvement of anemia and thrombocytopenia with low/intermediate-1 MDS.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Female; Humans; Hydroxycholecalciferols; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Vitamin K 2

Vitamin K2 induces differentiation of leukemic cell lines and apoptosis of immature blasts in myelodysplastic syndrome (MDS). We recently reported a case of MDS-refractory anemia (MDS-RA) with trilineage hematologic response to oral administration of menatetrenone, a vitamin K2 analog. To determine a possible role of this agent in treatment of MDS-RA, we conducted a prospective randomized trial assessing the safety and efficacy of menatetrenone. A total of 18 consecutive patients newly diagnosed with MDS-RA were randomized to receive either 45 mg of oral menatetrenone (group 1) or no menatetrenone (group 2). Administration of menatetrenone was well tolerated. Of the nine patients in group 1 (56%), five improved with menatetrenone treatment while only one (11%) of the group 2 patients improved. Three patients (33%) showed a major response in absolute neutrophil count (ANC), two (22%) showed a major response in hemoglobin concentration, and two of the nine (22%) showed a major response in platelet count. The ANC of group 1 patients rose after treatment, while that of group 2 patients decreased slightly at follow-up after 16 weeks ( p=0.03). Significant improvement was also seen in final platelet count ( p=0.01), but not in hemoglobin concentration. Given the absence of toxicity, menatetrenone can be recommended for all patients with MDS-RA.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anemia, Refractory; Cell Count; Female; Hematopoiesis; Hemostatics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Vitamin K 2

Vitamin K2 (VK2) can improve cytopenia in some patients with myelodysplastic syndrome (MDS). Although it is well known that VK2 induces differentiation and apoptosis in acute myeloid leukemia (AML) cell lines, little is known about its effect on normal hematopoietic progenitors. The effects of VK2 on primary myeloid and erythroid progenitors were examined. Mobilized CD34-positive cells from peripheral blood were used for the examination of myeloid lineage cells, and erythroid progenitors purified from peripheral blood were used for erythroid lineage cells. VK2 upregulated the expressions of myeloid markers CD11b and CD14, and increased the mRNA expression levels of CCAAT/enhancer binding protein-α (C/EBPα) and PU.1 in myeloid progenitors. In erythroid progenitors, VK2 did not show a significant effect on differentiation. However, VK2 exhibited an anti-apoptotic effect on erythroid progenitors under erythropoietin depletion. This anti-apoptotic effect was restricted to normal erythroid progenitors and was not shown in erythroleukemic cell line AS-E2. Steroid and xenobiotic receptor (SXR), which was recently identified as a receptor of VK2, was expressed on myeloid progenitors, and the SXR agonist rifampicin (RIF) also upregulated CD11b and CD14 expressions on myeloid progenitors. These results indicate that SXR is involved in the effect of VK2 on myeloid progenitors. The major effect of VK2 on myeloid progenitors was promoting differentiation, whereas its anti-apoptotic effect seemed to be dominant in erythroid progenitors. Although the detailed mechanism of VK2's effect on differentiation or apoptosis of hematopoietic progenitors remains unknown, the effect of VK2 therapy in patients with MDS could be partly explained by these mechanisms.

Topics: Antigens, Differentiation; Apoptosis; Cell Differentiation; Erythroid Precursor Cells; Female; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Myeloid Progenitor Cells; Neoplasm Proteins; Vitamin K 2; Vitamins

The study was aimed to investigate the possible mechanism of vitamin K(2) (VK(2)) on myelodysplastic syndrome (MDS) cell line MUTZ-1 in vitro. The flow cytometry was used to analyze apoptosis rate and the change of cell cycle. The expression of apoptosis-related genes bcl-2, survivin and bax were detected by reverse transcription-polymerase chain reaction (RT-PCR). The activity of caspase-3 was detected by chemiluminescence assay. The results indicated that the apoptosis peak on FCM and positive Annexin-V FITC on cell membrane showed that VK(2) induced apoptosis of MUTZ-1 cells in a dose-and-time-dependent manner, S and G(2) cell decrement, G(0)/G(1) cell arrest, VK(2) significantly down-regulated the expression of bcl-2 and survivin, but had no effect on the expression of bax, the activity of caspase-3 was significantly increased. It is concluded that VK(2) induces apoptosis of MUTZ-1 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2 and survivin may play important roles in the process of apoptosis induction.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Line, Tumor; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Myelodysplastic Syndromes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Survivin; Vitamin K 2

Vitamin K2 (VK2) effectively induces apoptosis in leukemia cell lines, including HL-60 and U937. However, combined treatment of cells with VK2 plus 1alpha,25-dihydroxy vitamin D3 (VD3) resulted in suppression of VK2-inducing apoptosis and pronounced induction of monocytic differentiation as compared with that by VD3 alone. After achieving monocytic differentiation by pre-exposure to VK2 and VD3, the cells became resistant to various apoptotic stimuli including VK2- and H2O2-treatment and serum deprivation. Accumulation of cytoplasm p21CIP1 along with disappearance of nuclear p21CIP1 was detected in cells in response to 96-h treatment with VK2 plus VD3. A stable transfectant, U937-deltaNLS-p21CIP1, which lacked the nuclear localization signal of p21CIP1 and showed overexpression of cytoplasm p21CIP1 without monocytic differentiation, was resistant to apoptosis. These data suggest that a change of intracellular distribution of p21CIP1 from nucleus to cytoplasm along with differentiation appears to be anti-apoptotic. Clinical benefits of using VK2 for treatment of patients with leukemia and myelodysplastic syndrome (MDS) have been reported. Our data suggest that VK2 plus VD3 may be an effective combination for differentiation-based therapy for leukemia and also MDS whose cytopenias are mediated though apoptosis.

Topics: Apoptosis; Calcitriol; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cytoplasm; Flow Cytometry; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Hydrogen Peroxide; Immunoblotting; Immunoprecipitation; Leukemia; MAP Kinase Kinase 4; Models, Biological; Monocytes; Myelodysplastic Syndromes; Time Factors; Transfection; U937 Cells; Vitamin K 2

To study the effects and possible mechanism of Vitamin K(2) (VK(2)) in the treatment of MDS-JSN04 cells, the changes of morphologic features of MDS-JSN04 cells were investigated by cytomorphology, the apoptosis of MDS-JSN04 cells was observed by transmission electron microscope; cellular proliferation was determined by the MTT assay; cell apoptosis, cell cycle shift and expression of myeloid-specific differentiation antigen (CD11b, CD13) were analyzed by flow cytometry (FCM). The expression of apoptosis-related genes bcl-2, survivin and bax were detected by retrotranscriptase polymerase chain reaction (RT-PCR); the activity of caspase-3 was determined by chemiluminescence assay. The results showed that the typical apoptotic morphological features appeared in cells treated with VK(2) for 72 hours; VK(2) induced apoptosis of MDS-JSN04 cells and in a dose-and-time-dependent manner, G(0)/G(1) cell arrest and significantly down-regulated the expression of bcl-2 and survivin, but had no effect on the expression of bax; the activity of caspase-3 significantly increased. It is concluded that VK(2) induces apoptosis of MDS-JSN04 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2, survivin may play an important role in this process.

Topics: Apoptosis; bcl-2-Associated X Protein; Caspase 3; CD11b Antigen; CD13 Antigens; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Luminescent Measurements; Microscopy, Electron, Transmission; Microtubule-Associated Proteins; Myelodysplastic Syndromes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Survivin; Vitamin K 2

Topics: Aged; Arachidonic Acids; Blood Transfusion; Bone Marrow; Cyclosporine; Hemostatics; Humans; Male; Myelodysplastic Syndromes; Platelet Count; Treatment Outcome; Vitamin K 2

Vitamin K2 is reported to induce apoptosis or differentiation of leukemic cell lines in vitro. We administered a vitamin K2 analog, menatetrenone, at 45 mg daily to 23 patients with myelodysplastic syndrome (MDS): 13 patients with RA, 2 with RARS, 6 with RAEB and 2 with RAEB-T. Good response (GR) and partial response (PR) were defined as an increase of hemoglobin concentration exceeding 2 g/dl and 1-2 g/dl without transfusion, respectively. Six of the RA patients showed improvement of anemia (GR, 3 patients; PR, 3 patients). RA patients who did not have a hypocellular bone marrow and were transfusion-independent tended to be responsive to vitamin K2 therapy in combination with vitamin D3 or anabolic steroids. No adverse effect of vitamin K2 was observed, and the time required to obtain the hematological response was short, being 3 months on average. We believe that vitamin K2 therapy has potential as a treatment for patients with MDS.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Vitamin K 2

Topics: Acute Disease; Adult; Aged; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Multicenter Studies as Topic; Myelodysplastic Syndromes; Pilot Projects; Vitamin K; Vitamin K 2

Geranylgeraniol, a polyprenylalcohol composing the side chain of vitamin K2 (VK2), was previously reported to be a potent inducer of apoptosis in tumor cell lines (Ohzumi H et al, J Biochem 1995; 117: 11-13). We examined the apoptosis-inducing ability of VK2 (menaquinone 3 (MK3), MK4 and MK5) and its derivatives such as phytonadione (VK1), as well as polyprenylalcohols with side chains of various lengths including farnesol (C15-OH; FO), geranylgeraniol (C20-OH; GGO), and geranylfarnesol (C25-OH; GFO) toward leukemia cells in vitro. MK3, MK4, MK5 and GFO (at 10 microM) showed a potent apoptosis-inducing activity for all freshly isolated leukemia cells tested and for leukemia cell lines such as NB4, an acute promyelocytic leukemia (APL)-derived cell line and MDS92, a cell line derived from a patient with myelodysplastic syndrome, although there were some differences depending on the cells tested. In contrast, VK1 showed no effect on any of the leukemia cells. The combination of MK5 plus all-trans retinoic acid (ATRA) resulted in enhanced induction of apoptosis in both freshly isolated APL cells and NB4 cells as compared to each reagent alone. These data suggest the possibility of using VK2 and its derivatives for the treatment of myelogenous leukemias, including APL.

Topics: Apoptosis; Bone Marrow; Diterpenes; Drug Synergism; Farnesol; Flow Cytometry; Gefarnate; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Molecular Structure; Myelodysplastic Syndromes; Structure-Activity Relationship; Tretinoin; Tumor Cells, Cultured; Vitamin K; Vitamin K 1; Vitamin K 2