Corilagin exhibits differential anticancer effects through the modulation of STAT3/5 and MAPKs in human gastric cancer cells.

Corilagin (CLG) is a hydrolyzable tannin and possesses various pharmacological activities. Here, we investigated the impact of CLG as an anti-tumor agent against human gastric tumor cells. We observed that CLG could cause negative regulation of JAKs-Src-STAT3/5 signaling axis in SNU-1 cells, but did not affect these pathways in SNU-16 cells. Interestingly, CLG promoted the induction of mitogen-activated protein kinases (MAPKs) signaling pathways in only SNU-16 cells, but not in the SNU-1 cells. CLG exhibited apoptotic effects that caused an increased accumulation of the cells in sub-G1 phase and caspase-3 activation in both SNU-1 and SNU-16 cell lines. We also noticed that CLG and docetaxel co-treatment could exhibit significantly enhanced apoptotic effects against SNU-1 cells. Moreover, the combinations treatment of CLG and docetaxel markedly inhibited cell growth, phosphorylation of JAK-Src-STAT3 and induced substantial apoptosis. Additionally, pharmacological inhibition of JNK, p38, and ERK substantially blocked CLG-induced activation of MAPKs, cell viability, and apoptosis, thereby implicating the pivotal role of MAPKs in the observed anti-cancer effects of CLG. Taken together, our data suggest that CLG could effectively block constitutive STAT3/5 activation in SNU-1 cells but induce sustained MAPKs activation in SNU-16 cells.

Abrogation of STAT3 activation cascade by Ginkgolide C mitigates tumourigenesis in lung cancer preclinical model.

OBJECTIVES: Ginkgolide C (GGC) isolated from Ginkgo biloba (Ginkgoaceae) leaf can demonstrate pleiotropic pharmacological actions. However, its anti-oncogenic impact in non-small cell lung cancer (NSCLC) model has not been reconnoitered. As signal transducer and activator of transcription 3 (STAT3) cascade can promote tumour growth and survival, we contemplated that GGC may interrupt this signalling cascade to expend its anti-cancer actions in NSCLC. METHODS: The effect of GGC on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation and apoptosis was examined. The in-vivo effect of GGC on the growth of human NSCLC xenograft tumours in athymic nu/nu female mice was also investigated. KEY FINDINGS: GGC attenuated the phosphorylation of STAT3 and STAT3 upstream kinases effectively. Exposure to pervanadate modulated GGC-induced down-regulation of STAT3 activation and promoted an elevation in the level of PTPε protein. Indeed, silencing of the PTPε gene reversed the GGC-promoted abrogation of STAT3 activation and apoptosis. Moreover, GGC exposure significantly reduced NSCLC tumour growth without demonstrating significant adverse effects via decreasing levels of p-STAT3 in mice tissues. CONCLUSIONS: Overall, the findings support that GGC may exhibit anti-neoplastic actions by mitigation of STAT3 signalling cascade in NSCLC.

Brassinin enhances the anticancer actions of paclitaxel by targeting multiple signaling pathways in colorectal cancer cells.

Brassinin (BSN), a precursor of phytoalexins, extracted from Chinese cabbage has been reported to act as a promising anti-neoplastic agent. However, the effects of BSN on colon cancer cells and its underlying mechanisms have not been fully elucidated. This study aimed at investigating the anti-neoplastic impact of BSN and its possible synergistic effect with paclitaxel on colon cancer cells. The effect of BSN on Janus-activated kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways and its downstream functions was deciphered using diverse assays in colon carcinoma cells. We found that BSN displayed significant cytotoxic effect and suppressed cell proliferation on colon carcinoma cells. Additionally, it was noted that BSN modulated oncogenic gene expression and induced apoptosis through down regulating multiple oncogenic signaling cascades such as JAKs/STAT3 and PI3K/Akt/mTOR simultaneously. Besides, BSN-paclitaxel combination significantly increased cytotoxicity and induced apoptosis synergistically as compared with individual treatment of both the agents. Overall, our findings indicate that BSN may be a novel candidate for anti-colon cancer targeted therapy.

Identification of protocatechuic acid as a novel blocker of epithelial-to-mesenchymal transition in lung tumor cells.

Protocatechuic acid (PA) is widely distributed and commonly occurring natural compound that can exert antioxidant, anti-inflammatory, as well as anti-cancer effects. Epithelial-to-mesenchymal transition (EMT) is important cellular process that can control tumor invasion and metastasis. Here, we investigated whether PA can modulate the EMT process in basal and transforming growth factorß-induced A549 and H1299 cells. We found that PA suppressed expression of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin), MMP-9, MMP-2, twist, and snail but stimulated the levels of epithelial markers (E-cadherin and Occludin). In addition, PA can affect TGFß-induced expression of both mesenchymal and epithelial markers. Moreover, PA abrogated migratory and invasive potential of tumor cells by reversing the EMT process. Furthermore, we found that PA suppressed EMT process by abrogating the activation of PI3K/Akt/mTOR signaling cascade in lung cancer cells.

Corilagin Represses Epithelial to Mesenchymal Transition Process Through Modulating Wnt/ß-Catenin Signaling Cascade.

Corilagin (CLG), a major component of several medicinal plants, can exhibit diverse pharmacological properties including those of anti-cancer, anti-inflammatory, and hepatoprotective qualities. However, there are no prior studies on its potential impact on the epithelial-to-mesenchymal transition (EMT) process. EMT can lead to dissemination of tumor cells into other organs and promote cancer progression. Hence, we aimed to investigate the effect of CLG on EMT and its mechanism(s) of action in tumor cells. We noted that CLG reduced the expression of various epithelial markers and up-regulated the expression of Occludin and E-cadherin in both basal and TGFß-stimulated tumor cells. CLG treatment also abrogated cellular invasion and migration in colon and prostate carcinoma cells. In addition, CLG effectively attenuated the Wnt/ß-catenin signaling cascade in TGFß-stimulated cells. Overall, our study suggests that CLG may function as and effective modulator of EMT and metastasis in neoplastic cells.

Theacrine attenuates epithelial mesenchymal transition in human breast cancer MDA-MB-231 cells.

Theacrine, a purine alkaloid structurally similar to caffeine, has recently become of interest as a potential therapeutic compound. Here, we investigated the antimetastatic potential of theacrine on human breast cancer MDA-MB-231 cells. We observed that theacrine can reverse epithelial-to-mesenchymal transition (EMT), which resulted in a decrease in the levels of mesenchymal markers (Fibronectin, Vimentin, N-cadherin, Twist, and Snail) and an increase in the levels of epithelial markers (Occludin and E-cadherin) in the cells. Additionally, theacrine attenuates TGF-ß-induced EMT, cell adhesion, migration, and invasion in MDA-MB-231 cells. Overall, our results suggest that theacrine may inhibit the breast cancer cell metastasis by reversing the EMT process.