vitamin-k-semiquinone-radical and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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

Quinone-induced cell death is often attributed to oxidative stress during which the formation of DNA strand breaks is thought to play an important role. In this study, extensive DNA damage was observed in human chronic myelogenous leukemic cells (K562) exposed for 15 minutes to low concentrations (15-100 microM) of the redox cycling quinones 2,3-dimethoxy-1,4-naphthoquinone (2,3-diOMe-1,4-NQ) and menadione. However, DNA strand breakage and cell death could not be attributed to oxidative stress as the intracellular level and redox status of the reducing equivalents NADP(H) and GSH were unaffected. The intracellular level of NAD+ was found to correlate well with the extent of DNA repair (r = 0.93, P < 0.02) and cell proliferation (r = 0.96, P < 0.01) in cells exposed to the quinones. In contrast, a significant decrease in the level of intracellular ATP was only observed in cells exposed to menadione (50-100 microM). These results suggest that redox cycling quinones are capable of inducing DNA damage in mammalian cells by a mechanism that does not involve oxidative stress. Following DNA damage, cell death is dependent on the availability of NAD+, which may be key to the rapid repair of strand breaks.

Topics: Adenosine Triphosphate; Cell Death; Cell Division; DNA Damage; DNA, Neoplasm; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; NAD; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Substrate Cycling; Tumor Cells, Cultured; Vitamin K

Utility of drug response modulators to increase therapeutic:toxic ratio of anticancer drugs in the treatment of refractory malignancies is becoming desirable. In this study, we have attempted to potentiate the tumor cell killing ability of Adriamycin (ADR) against chronic myeloid leukemia cells (CML), in the presence of vitamin K3. Cell growth was evaluated by the MTT assay and the 3H-thymidine incorporation inhibition assay. A highly significant (p less than 0.001) inhibition of cell survival and 3H-thymidine incorporation was effected in CML cells exposed to the combination of ADR and vitamin K3. When the CML cells were treated with ADR and vitamin K3 simultaneously, a greater fragmentation of the intact DNA was revealed as observed by the enhanced formation of DNA single strand breaks. Results demonstrate the therapeutic significance of employing vitamin K3 as an adjuvant in CML chemotherapy with ADR.

Topics: Cell Survival; DNA Damage; Doxorubicin; Drug Therapy, Combination; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Tumor Cells, Cultured; Vitamin K