Brevilin A exerts anti-colorectal cancer effects and potently inhibits STAT3 signaling invitro.

Colorectal cancer (CRC) is the third most common cause of cancer-related morbidity worldwide, with an estimated of 1.85 million new cases and 850,000 deaths every year. Nevertheless, the current treatment regimens for CRC have many disadvantages, including toxicities and off-targeted side effects. STAT3 (signal transducer and activator of transcription 3) has been considered as a promising molecular target for CRC therapy. Brevilin A, a sesquiterpene lactone compound rich in Centipedae Herba has potent anticancer effects in nasopharyngeal, prostate and breast cancer cells by inhibiting the STAT3 signaling. However, the anti-CRC effect of brevilin A and the underlying mechanism of action have not been fully elucidated. In this study, we aimed to investigate the involvement of STAT3 signaling in the anti-CRC action of brevilin A. Here, HCT-116 and CT26 cell models were used to investigate the anti-CRC effects of brevilin A in vitro. HCT-116 cells overespressing with STAT3 were used to evaluate the involvement of STAT3 signaling in the anti-CRC effect of brevilin A. Screening of 49 phosphorylated tyrosine kinases in the HCT-116 cells after brevilin A treatment was performed by using the human phospho-receptor tyrosine kinase (phospho-RTK) array. Results showed that brevilin A inhibited cell proliferation and cell viability, induced apoptosis, reduced cell migration and invasion, inhibited angiogenesis, lowered the protein expression levels of phospho-Src (Tyr416), phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), and inhibited STAT3 activation and nuclear localization. Brevilin A also significantly reduced the protein expression levels of STAT3 target genes, such as MMP-2, VEGF and Bcl-xL. More importantly, over-activation of STAT3 diminished brevilin A's effects on cell viability. All these results suggest that brevilin A exerts potent anti-CRC effects, at least in part, by inhibiting STAT3 signaling. Our findings provide a strong pharmacological basis for the future exploration and development of brevilin A as a novel STAT3-targeting phytotherapeutic agent for CRC treatment.

Centipeda minima: An update on its phytochemistry, pharmacology and safety.

ETHNOPHARMACOLOGICAL RELEVANCE: Centipeda minima (CM), the dried whole plant of Centipeda minima (L.) A. Braun and Aschers, has been used as a traditional Chinese medicinal herb for thousands of years for the treatments of rhinitis, sinusitis, cough and asthmatic diseases. This review aimed to evaluate the therapeutic potential of CM by summarizing its phytochemistry, pharmacology, clinical application and safety. METHODS: This review summarizes the published studies on CM in the Chinese Pharmacopoeia and literature databases including PubMed, Web of Science, Baidu Scholar, Wiley and China Knowledge Resource Integrated Database (CNKI), as well as the research articles on the phytochemistry, pharmacology, clinical application and safety of CM. RESULTS: A total of 191 compounds have been isolated and identified from CM, including terpenes, flavonoids, sterols, phenols, organic acids and volatile oils. In addition, the pharmacological effects of CM, such as anti-cancer, anti-inflammatory and anti-bacterial activities, have also been evaluated by both in vitro and in vivo studies. The signaling pathways and mechanisms of action underlying the anti-cancer effects of CM have been revealed. Clinical applications of CM mainly include rhinitis and sinusitis, gynecological inflammation, cough, as well as asthma. CONCLUSION: CM is a medicinal herb that possesses many therapeutic effects. Cutting-edge technology and system biology could provide us a more comprehensive understanding of the therapeutic effects, constituting components and toxicity of CM, which are the prerequisites for its translation into therapeutics for various disease treatments.

Medicinal herbs and bioactive compounds overcome the drug resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases. Patients harboring epidermal growth factor receptor (EGFR) mutations usually develop resistance to treatment with frontline EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The present review summarizes the current findings and delineates the molecular mechanism of action for the therapeutic effects of herbal extracts and phytochemicals in overcoming EGFR-TKI resistance in NSCLC. Novel molecular targets underlying EGFR-TKI resistance in NSCLC are also discussed. This review provides valuable information for the development of herbal bioactive compounds as alternative treatments for EGFR-TKI-resistant NSCLC.

The optimal dose of arsenic trioxide induced opposite efficacy in autophagy between K562 cells and their initiating cells to eradicate human myelogenous leukemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Arsenic trioxide (As2O3), a main component of arsenolite which is a common traditional Chinese medicine (TCM) wildly used as a therapeutic agent for more than 2400 years in china, has been accepted as a standard treatment for the patients with acute promyelocytic leukemia (APL) based on the principle in TCM of "using a poison to fight against other poisons or malignancy illnesses". However, it remains unknown that which mechanism is actually responsible for the therapeutic effects against these blood malignancies. AIM OF THE STUDY: The purpose of this study was to explore the actual mechanism that ATO exerts its effects in K562 cells and their initiating cells (K562s). MATERIALS AND METHODS: K562s cells were separated and enriched for CD34+/CD38- cells using magnetic microbeads. Cell proliferation was determined by incorporation of BrdU. Cell apoptosis was evaluated by Annexin-V binding and PI uptake. Autophagy was estimated by acridine orange and immunofluorescence staining of LC3-B and p62. MC colonic formation was used to examine cell self-renew. ROS generation inside living cells was measured by DCFH-DA. Cell differentiation was assessed by the benzidine staining. The SA-ß-gal assay was used to detect cell senescence. Protein expression was examined by western blotting and immunohistochemical staining. RESULTS: K562s cells were stronger in self-renew and resistance to ATO cytotoxicity and starvation-induced apoptosis than K562 cells. Unexpectedly, we found that ATO at a dose of 0.5µM which had no effect on cell proliferation resulted in maximum suppression on self-renew in both cells and maximum starvation-induced apoptosis in K562s cells but minimum starvation-induced apoptosis in K562 cells. Next, we found that ATO no more than 0.5µM selectively induced K562s cell differentiation indicated by benzidine staining, γ-globin and CD235a expression. More importantly, we found that ATO no more than 0.5µM led to opposite efficacy in autophagy between K562 and K562s cells, and the opposite autophagy could induced late-phase senescence in both cells. Finally, we used the optimal dose of ATO to eradicate leukemia cells and obtained a satisfied therapeutic outcomes in vivo. CONCLUSIONS: Our results suggest that the used dose of ATO may determine the fate of cell differentiation senescence or malignant transformation, and the optimal dose of ATO induced opposite efficacy in autophagy between K562 cells and their initiating cells and ultimately leads both cells to late-phase senescence.

Oral kanglaite injection (KLTI) attenuates the lung cancer-promoting effect of high-fat diet (HFD)-induced obesity.

Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity.