Lévy, “Very-low-dose combination of the angiotensinconverting enzyme inhibitor perindopril and the diuretic indapamide induces an early and sustained increase in neovascularization in rat ischemic legs

ABSTRACT After acute ischemia of tissues, neovascularization must be sufficient and fast enough to preserve tissue integrity and organ function, and may thus be considered as a therapeutic strategy. This study examined the possible role of the very-low-dose combination of perindopril (angiotensin-converting enzyme inhibitor) and indapamide (diuretic), used first-line in the treatment of essential hypertension, on ischemia-induced angiogenesis. Ischemia was produced by artery femoral occlusion in rats treated or not with the very-low-dose combination (perindopril 0.76 mg/kg/day ϩ indapamide 0.24 mg/kg/day) or each component given alone at the same dosage for 3 and 28 days. At day 3, angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio by, respectively, 1.9-fold and 1.5-fold in rats treated with the very-low-dose combination when compared with controls (p Ͻ 0.05). This was associated with an increas

Synergistic effects of eIF4A and MEK inhibitors on proliferation of NRAS-mutant melanoma cell lines

Activating mutations of the NRAS (neuroblastoma rat sarcoma viral oncogene) protein kinase, present in many cancers, induce a constitutive activation of both the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway and the PI(3)K-AKT-mTOR, pathway. This in turn regulates the formation of the eIF4F eukaryotic translation initiation complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNAs. Small molecules targeting MEK (MEKi: MEK inhibitors) have demonstrated activity in NRAS-mutant cell lines and tumors, but resistance sets in most cases within months of treatment. Using proximity ligation assays, that allows visualization of the binding of eIF4E to the scaffold protein eIF4G, generating the active eIF4F complex, we have found that resistance to MEKi is associated with the persistent formation of the eIF4F complex in MEKi-treated NRAS-mutant cell lines. Furthermore, inhibiting the eIF4A component of the eIF4F complex, with a small molecule of the flavagline/rocaglate family, synergizes with inhibiting MEK to kill NRAS-mutant cancer cell lines