The oleanolic acid derivative, 3-O-succinyl-28-O-benzyl oleanolate, induces apoptosis in B16–F10 melanoma cells via the mitochondrial apoptotic pathway
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AutorReyes Zurita, Fernando Jesús; Medina-O'Donnell, Marta; Ferrer-Martín, Rosa María; Rufino Palomares, Eva Encarnación; Martín-Fonseca, Samuel; Rivas, Francisco; Martínez, Antonio; García Granados López de Hierro, Andrés; Pérez-Jiménez, Amalia; García-Salguero, Leticia; Peragón Sánchez, Juan; Mokhtari, Khalida; Medina, Pedro P.; Parra Sánchez, Andrés; Lupiáñez Cara, José Antonio
Royal Society of Chemistry
Oleanolic acidMelanomaTreatmentOlive pomaceApoptosisAntineoplastic agentsTriterpenoidTherapeutics
Reyes-Zurita, F.J.; et al. The oleanolic acid derivative, 3-O-succinyl-28-O-benzyl oleanolate, induces apoptosis in B16–F10 melanoma cells via the mitochondrial apoptotic pathway. RSC Advances, 6: 93590-93601 (2016). [http://hdl.handle.net/10481/45624]
PatrocinadorThis study was supported by grants Group BIO 157 from the Technology and Innovation Council of the Andalucian regional government and AGL2006-12210-C03-02/ALI, SAF2005-01627, ISCIII-RTICC (RD06/0020/0046) from the Spanish government and European Union FEDER funds.
Oleanolic acid (1) is a pentacyclic triterpene present in olive pomace, which is known to induce apoptosis and to have anti-tumor properties; however, high concentrations of this product are necessary to produce cytotoxic effects. The 3-O-succinyl-28-O-benzyl oleanolate derivative (4) presents greater cytotoxicity and apoptosis effects than its natural precursor, oleanolic acid, or its benzyl derivative (2). This study examines the response of B16–F10 melanoma cells to treatment with compound 4, in comparison to 1 and 3. Our studies show that treatment with 4 results in a significant inhibition of cell proliferation in a dose-dependent manner and causes apoptotic cell death. At concentrations inhibiting cell growth by 50% and 80%, compound 4 induces strong G0/G1 cell-cycle arrest, around 72–95% apoptosis, and mitochondrial disturbances confirmed by FACS analysis, which probably involve the activation of the intrinsic apoptotic route. Morphological changes including cell shrinkage, chromatin condensation, and loss of nuclear architecture were also observed. In this report, we demonstrated for the first time that in melanoma cancer cells, compound 4 exerts a significant anti-proliferation effect by inducing the apoptotic process with mitochondrial depolarization. These findings support the role of compound 4 as a new, potential therapeutic tool against aberrant cell proliferation in melanoma.