Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

Effect of red wine polyphenol dietary supplementation on two phase II enzymes in liver of hyperhomocysteinemic mice.

Hyperhomocysteinemia leads to diverse clinical manifestations, notably liver disease. The pathogenicity of homocysteine is believed to be due to its ability to produce oxidative stress. Paraoxonase-1 (Pon1), a phase I xenobiotic-metabolizing enzyme (XME) synthesized by liver with anti-oxidative properties within the circulating system is down regulated in case of hyperhomocysteinemia. In a previous study, we have shown that red wine polyphenol extract (PE) supplementation induces a decrease in plasma homocysteine level and an increase in hepatic Pon1 gene expression concomitant with an increase in hepatic and plasma Pon1 activity in a murine model of hyperhomocysteinemia. In the present study, we analyzed the effect of PE supplementation on two phase II XME: NAD(P)H:quinone oxidoreductase (Nqo1) and arylamine-N-acetyltransferase (Nat) family. We found that hyperhomocysteinemia leads to a decrease of hepatic Nqo1 gene expression and activity with a reversal effect of PE supplementation. We also found that hyperhomocysteinemia-induced decrease of peroxynitrite level is associated with an increase of hepatic total Nat activity mainly due to the Nat2 isoform with a reversal effect of PE supplementation. Our results show a beneficial effect of PE supplementation on two phase II enzymes which are altered in case of hyperhomocysteinemia.

Effects of catechin on homocysteine metabolism in hyperhomocysteinemic mice.

We have recently focused on the interaction between hyperhomocysteinemia, defined by high plasma homocysteine levels, and paraoxonase-1 expression and found a reduced activity of paraoxonase-1 associated with a reduced gene expression in the liver of cystathionine beta synthase (CBS) deficient mice, a murine model of hyperhomocysteinemia. As it has been demonstrated that polyphenolic compounds could modulate the expression level of the paraoxonase-1 gene in vitro, we have investigated the possible effect of flavonoid supplementation on the impaired paraoxonase-1 gene expression and activity induced by hyperhomocysteinemia and have evaluated the link with homocysteine metabolism. High-methionine diet significantly increased serum homocysteine levels, decreased hepatic CBS activity, and down-regulated paraoxonase-1 mRNA and its activity. However, chronic administration of catechin but not quercetin significantly reduced plasma homocysteine levels, attenuated the reduction of the hepatic CBS activity, and restored the decreased paraoxonase-1 gene expression and activity induced by chronic hyperhomocysteinemia. These data suggest that catechin could act on the homocysteine levels by increasing the rate of catabolism of homocysteine.