VITAMIN-K2 AND ITS DERIVATIVES INDUCE APOPTOSIS IN LEUKEMIA-CELLS ANDENHANCE THE EFFECT OF ALL-TRANS-RETINOIC ACID

Geranylgeraniol, a polyprenylalcohol composing the side chain of vitam in K2 (VK2), was previously reported to be a potent inducer of apoptos is in tumor cell lines (Ohzumi H et al, J Biochem 1995; 117: 11-13). W e 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 fa rnesol (C-15-OH; FO), geranylgeraniol (C-20-OH; GGO), and geranylfarne sol (C-25-OH; GFO) toward leukemia cells in vitro. MK3, MK4, MK5 and G FO (at 10 mu M) showed a potent apoptosis-inducing activity for all fr eshly isolated leukemia cells tested and for leukemia cell lines such as NB4, an acute promyelocytic leukemia (APL)-derived cell line and MD S92, a cell line derived from a patient with myelodysplastic syndrome, although there were some differences depending on the cells tested. I n contrast, VK1 showed no effect on any of the leukemia cells. The com bination of MK5 plus all-trans retinoic acid (ATRA) resulted in enhanc ed induction of apoptosis in both freshly isolated APL cells and NB4 c ells as compared to each reagent alone. These data suggest the possibi lity of using VK2 and its derivatives for the treatment of myelogenous leukemias, including APL.