Polyphenol rich fraction from Larrea divaricata and its main flavonoid quercetin-3-methyl ether induce apoptosis in lymphoma cells through nitrosative stress

MARTINO RENZO; BARREIRO ARCOS L; ALONSO MARÍA ROSARIO; SULSEN, VALERIA; CREMANSCHI G; ANESINI CLAUDIA

PHYTOTHERAPY RESEARCH

JOHN WILEY & SONS LTD

Lugar: LOndres; Año: 2016 vol. 30 p. 1128 - 1139

0951-418X

ABSTRACTLarrea divaricata is a plant with antiproliferative principles. We have previously identified the flavonoid quercetin-3-methyl ether (Q-3-ME) in an ethylacetate fraction (EA). Both the extract and Q-3-ME were found to be effective against the EL-4 T lymphoma cell line. However, the mechanism underlying the inhibition of tumor cells proliferation remains tobe elucidated. In this work we analyzed the role of nitric oxide (NO) in the induction of apoptosis mediated by Q-3-ME and EA. Both treatments were able to induce apoptosis in a concentration and time dependent manner. The western blot analysis revealed a sequential activation of caspases-9 and 3, followed by poly-(ADP-Ribose)-polymerase cleavage. EA and Q-3-ME lowered the mitochondrial membrane potential, showing the activation of the intrinsic pathway of apoptosis. Q-3-ME and EA increased NO production and inducible NO synthase expression in tumor cells. The involvement of NO in cell death was confirmedby the NOS inhibitor L-NAME. In addition, EA and Q-3-ME induced a cell cycle arrest in G0/G1 phase. These drugs did not affect normal cell viability. This data suggested that EA induce and increase in NO production that would lead to the cell cycle arrest and the activation of the intrinsic pathway of apoptosis