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Phytother Res. 2016 Jul;30(7):1128-36. doi: 10.1002/ptr.5615. Epub 2016 Apr 1.

Polyphenol-Rich Fraction from Larrea divaricata and its Main Flavonoid Quercetin-3-Methyl Ether Induce Apoptosis in Lymphoma Cells Through Nitrosative Stress.

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Instituto de Química y Metabolismo del Fármaco - IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 piso 2, 1113, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Av. A. Moreau de Justo 1600, piso 3, 1107AFF, Buenos Aires, Argentina.


Larrea divaricata is a plant with antiproliferative principles. We have previously identified the flavonoid quercetin-3-methyl ether (Q-3-ME) in an ethyl acetate 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 cell proliferation remains to be 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-dependent 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 confirmed by the nitric oxide synthases 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 and Q-3-ME induce an increase in NO production that would lead to the cell cycle arrest and the activation of the intrinsic pathway of apoptosis.


Larrea divaricata; T lymphoma cells; apoptosis; ethyl acetate fraction; nitric oxide; quercetin-3-methyl ether

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