Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.

Aromatic methyl ketones and cyclic asymmetric ketones underwent hydrophosphorylation with P-stereogenic H-P species in the presence of potassium carbonate to produce P,C-stereogenic tertiary α-hydroxyl phosphinates in excellent yields with up to 99 : 1 dr. The diastereoselectivity was induced by a reversible conversion of less stable stereomer of product to that of a more stable one via an equilibrium, which was confirmed by aldehyde/ketone exchanging reaction. Toward the exchange, aliphatic or aldehyde carbonyl were more active than aromatic or ketone carbonyls, respectively. The stability difference between the two diastereomers was controlled by the sizes of substituents linking to phosphorus or α-carbon.

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Background: Population-based estimates for prognosis among patients with liver metastases in newly diagnosed breast cancer are not generally available.Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, we identified 298,370 patients with breast cancer and 4,285 patients diagnosed with initial liver metastases between 2010 and 2014. Data were stratified according to subtype, age, and race. Multivariate logistic and Cox regression were used to identify predictors for the presence of initial liver metastases and prognostic factors, respectively. Kaplan-Meier procedure was used for survival analysis.Results: A total of 4,285 patients with initial liver metastases (1.4% of the entire cohort, 29.6% of the subset with metastatic disease) were identified. Patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive (4.4% of entire cohort, 52.5% of patients with metastatic disease to any distant site) and HR-positive HER2-positive (2.8% of entire cohort, 40.4% of patients with metastatic disease to any distant site) subtypes had highest incidence proportions. The median survival of patients with liver metastases in the entire cohort was 15.0 months. Patients with HR-positive HER2-positive subtype showed the longest median survival (31.0 months); however, patients with triplenegative subtype showed the shortest median survival (8.0 months).Conclusions: Our findings provide population-based estimates of epidemiologic characteristics and prognosis in breast cancer patients diagnosed with initial liver metastases.Impact: This study lends support to the diagnosis of the liver among patients at high risk of liver metastases, including those with HER2-positive and other systemic metastases.