Oleanolic Acid Initiates Apoptosis in Non-Small Cell Lung Cancer Cell Lines and Reduces Metastasis of a B16F10 Melanoma Model In Vivo

Drug resistance, a process mediated by multiple mechanisms, is a critical determinant for treating lung cancer. The aim of this study is to determine if oleanolic acid (OA), a pentacyclic triterpene present in several plants, is able to circumvent the mechanisms of drug resistance present in non-small cell lung cancer (NSCLC) cell lines and to induce their death.OA decreased the cell viability of the NSCLC cell lines A459 and H460 despite the presence of active, multidrug-resistant (MDR) MRP1/ABCC1 proteins and the anti-apoptotic proteins Bcl-2 and survivin. These effects are due to apoptosis, as evidenced by the capacity of OA to induce fragmentation of DNA and activate caspase 3. Induction of NSCLC cell death by OA cannot be explained by inhibition of the MDR proteins, since treatment with triterpene had little or no effect on the activity or expression of MRP1. Moreover, treatment with OA had no effect on the expression of the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic protein Bax, altering the Bcl-2/Bax balance towards a pro-apoptotic profile. OA also decreased the expression of the anti-apoptotic protein survivin. Furthermore, OA decreased the expression of the angiogenic vascular endothelial growth factor (VEGF) and decreased the development of melanoma-induced lung metastasis.Our data provide a significant insight into the antitumoral and antimetastatic activity of OA in NSCLC and suggest that including OA in the NSCLC regimens may help to decrease the number of relapses and reduce the development of metastases

M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination

The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia/macrophages, which can be polarized to distinct functional phenotypes: proinflammatory (M1) or anti-inflammatory/immunoregulatory (M2). Here we show that a switch from an M1- to M2-dominant response occurred within microglia and peripherally-derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 conditioned media, and impaired in vivo following intra-lesional M2 depletion. M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal, and in MS lesions that normally show remyelination. Blocking M2-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Our results therefore show that M2 polarization is essential for efficient remyelination and identify activin-A as a novel therapeutic target for CNS regeneration