Lipoxygenase inhibitors enhance tumor suppressive effects of jun proteins on v-myb-transformed monoblasts BM2

Inhibitors of arachidonic acid (AA) conversion were described as suppressors of proliferation and inducers of differentiation of various leukemic cells. Certain AA metabolites have been shown to cooperate with Jun proteins that are important factors controlling cell proliferation, differentiation and apoptosis. Using lipoxygenase (LOX) inhibitors of various specifity we studied possible participation of lipoxygenase pathway in regulation of proliferation and apoptosis of v-myb-transformed chicken monoblasts BM2 and its functional interaction with Jun proteins. We found that nordihydroguaiaretic acid (NDGA) and esculetin (Esc) negatively regulate proliferation of BM2 cells causing accumulation in either G0/G1-phase (nordihydroguaiaretic acid) or S-phase (esculetin) of the cell cycle. BM2 cells can be also induced to undergo growth arrest and partial differentiation by ectopic expression of Jun proteins. We demonstrated that lipoxygenase inhibitors further enforce tumor suppressive capabilities of Jun proteins by inducing either more efficient cell cycle block and/or apoptosis in BM2 cells. This suggests that there is a cross-talk between the lipoxygenase- and Jun-directed pathways in regulation of differentiation and proliferation of monoblastic cells. Thus pharmacologic agents that specifically block lipoxygenase-catalyzed activity and enforce the effects of differentiation-inducers may be important components in anti-tumor therapies.