Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

Present work mainly evaluated the inhibitory effects of lidamycin (LDM), an enediyne antibiotic, on angiogenesis or glioma-induced angiogenesis in vitro and in vivo, especially its synergistic anti-angiogenesis with temozolomide (TMZ). LDM alone efficiently inhibited proliferations and induced apoptosis of rat brain microvessel endothelial cells (rBMEC). LDM also interrupted the tube formation of rat brain microvessel endothelial cells (rBMEC) and rat aortic ring spreading. The blockade of rBMEC invasion and C6 cell-induced rBMEC migration by LDM was associated with decrease of VEGF secretion in a co-culture system. TMZ dramatically potentiated the effects of LDM on anti-proliferation, apoptosis induction, and synergistically inhibited angiogenesis events. As determined by western blot and ELISA, the interaction of tumor cells and the rBMEC was markedly interrupted by LDM plus TMZ with synergistic regulations of VEGF induced angiogenesis signal pathway, tumor cell invasion/migration, and apoptosis signal pathway. Immunofluorohistochemistry of CD31 and VEGF showed that LDM plus TMZ resulted in synergistic decrease of microvessel density (MVD) and VEGF expression in human glioma U87 cell subcutaneous xenograft. This study indicates that the high efficacy of LDM and the synergistic effects of LDM plus TMZ against glioma are mediated, at least in part, by the potentiated anti-angiogenesis.