Cancer stem cells (CSC) are the primary cell type responsible for metastasis and relapse. ABC-transporters are integral membrane proteins involved in the translocation of substrates across membranes protecting CSC from chemotherapeutic agents. A plant extract derived from C. spinosa (P2Et) previously investigated for its antitumor activity has been shown to reduce lung and spleen metastasis in mice that have been transplanted with breast cancer cells, suggesting that P2Et has a significant activity against cancer stem cells (CSC). P2Et extract was thoroughly characterized by HPLC/MS. The cytotoxicity of P2Et extract was evaluated using a MTT assay in human and murine cell lines with different profiles of resistance, by Pgp overexpression or by enrichment in cancer stem cells. The synergistic effect of P2Et with doxorubicin was evaluated in vitro in several cell lines and in vivo in mice transplanted with TS/A cells, a highly resistant cell line and enriched in CD44[Formula: see text]CD24[Formula: see text]CSC. The chromatographic fingerprint of P2Et extract revealed 13 gallotannins. We also found that P2Et extract was cytotoxic to cells regardless of their resistant phenotype. Similarly, complementary activities were observed as drug efflux reversion and antioxidant activity. Short-treatment with P2Et extract, revealed a synergistic effect with doxorubicin in resistant cell lines. In vivo the P2Et increases mice survival in a TS/A breast cancer model associated with augmentation of calreticulin expression. Our results suggest that P2Et treatment could be used as adjuvant along with conventional chemotherapy to treat tumors with a MDR phenotype or with high frequency of CSC.
The application of a domino radical bicyclization for
the synthesis
of compounds containing the 1-azaspiro[4.4]nonane skeleton in 11–67%
yields as a mixture of diastereomers is described (trans configuration preference). This process involved formation and capture
of alkoxyaminyl radicals. For this purpose, O-benzyl
oxime ethers with a brominated or iodinated aromatic ring or a terminal
alkynyl group and an alkenyl moiety were employed as starting materials.
The bicyclization was initiated by 2,2′-azobisisobutyronitrile
or triethylborane and promoted by Bu3SnH. The best results
were obtained with O-benzyl oxime ethers containing
an alkenyl moiety tethered to electron withdrawing groups or aryl
substituents, whereas oxime radical precursor attached to methyl-substituted
olefin precluded the capture of alkoxyaminyl radical, giving rise
mainly to monocyclized product.
Parkinson's disease (PD) is a neurodegenerative pathology characterized by resting tremor, rigidity, bradykinesia, and loss of dopamine-producing neurons in the pars compacta of the substantia nigra in the central nervous system (CNS) that result in dopamine depletion in the striatum. Oxidative stress has been documented as a key pathological mechanism for PD. Epidemiological studies have shown that smokers have a lower incidence of PD. In this aspect, different studies have shown that nicotine, a chemical compound found in cigarette, is capable of exerting beneficial effects in PD patients, but it can hardly be used as a therapeutic agent because of its inherent toxicity. Several studies have suggested that the use of nicotine analogs can have the same benefits as nicotine but lack its toxicity. In this study, we assessed the effects of two nicotine analogs, (E)-nicotinaldehyde O-cinnamyloxime and 3-(pyridin-3-yl)-3a,4,5,6,7,7a-hexahidrobenzo[d]isoxazole, in an in vitro model of PD. Initially, we performed a computational prediction of the molecular interactions between the nicotine analogs with the α7 nicotinic acetylcholine receptor (nAChR). Furthermore, we evaluated the effect of nicotine, nicotine analogs and rotenone on cell viability and reactive oxygen species (ROS) production in the SH-SY5Y neuronal cell line to validate possible protective effects. We observed that pre-treatment with nicotine or (E)-nicotinaldehyde O-cinnamyloxime (10 μM) improved cell viability and diminished ROS production in SH-SY5Y cells insulted with rotenone. These findings suggest that nicotine analogs have a potential protective effect against oxidative damage in brain pathologies.
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