Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies.

Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as "colorectal cancer" AND "phenolic compounds", "colorectal cancer" AND "polyphenol", "colorectal cancer" AND "phenolic acids", "colorectal cancer" AND "flavonoids", "colorectal cancer" AND "stilbene", and "colorectal cancer" AND "lignan" from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.

IL-13 and the hydroperoxy fatty acid 13(S)HpODE play crucial role in inducing an apoptotic pathway in cancer cells involving MAO-A/ROS/p53/p21 signaling axis.

This study depicted the effect of IL-13 and 13(S)HpODE (the endogenous product during IL-13 activation) in the process of cancer cell apoptosis. We examined the role of both IL-13 and 13(S)HpODE in mediating apoptotic pathway in three different in vitro cellular models namely A549 lung cancer, HCT116 colorectal cancer and CCF52 GBM cells. Our data showed that IL-13 promotes apoptosis of A549 lung carcinoma cells through the involvement of 15-LO, PPARγ and MAO-A. Our observations demonstrated that IL-13/13(S)HpODE stimulate MAO-A-mediated intracellular ROS production and p53 as well as p21 induction which play a crucial role in IL-13-stimulated A549 cell apoptosis. We further showed that 13(S)HpODE promotes apoptosis of HCT116 and CCF52 cells through the up-regulation of p53 and p21 expression. Our data delineated that IL-13 stimulates p53 and p21 induction which is mediated through 15-LO and MAO-A in A549 cells. In addition, we observed that PPARγ plays a vital role in apoptosis as well as in p53 and p21 expression in A549 cells in the presence of IL-13. We validated our observations in case of an in vivo colon cancer tumorigenic study using syngeneic mice model and demonstrated that 13(S)HpODE significantly reduces solid tumor growth through the activation of apoptosis. These data thus confirmed that IL-13 > 15-LO>13(S)HpODE > PPARγ>MAO-A > ROS > p53>p21 axis has a major contribution in regulating cancer cell apoptosis and further identified 13(S)HpODE as a potential chemo-preventive agent which can improve the efficacy of cancer treatment as a combination compound.

Alkaloid-rich fraction of Ervatamia coronaria sensitizes colorectal cancer through modulating AMPK and mTOR signalling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Ervatamia coronaria, a popular garden plant in India and some other parts of the world is known traditionally for its anti-inflammatory and anti-cancer properties. The molecular bases of these functions remain poorly understood. AIM OF THE STUDY: Efficacies of the existing therapies for colorectal cancer (CRC) are limited by their life-threatening side effects and unaffordability. Therefore, identifying a safer, efficient, and affordable therapeutic is urgent. We studied the anti-CRC activity of an alkaloid-rich fraction of E. coronaria leaf extracts (AFE) and associated underlying mechanism. MATERIALS AND METHODS: Activity guided solvant fractionation was adopted to identify the activity in AFE. Different cell lines, and tumor grown in syngeneic mice were used to understand the anti-CRC effect. Methodologies such as LCMS, MTT, RT-qPCR, immunoblot, immunohistochemistry were employed to understand the molecular basis of its activity. RESULTS: We showed that AFE, which carries about six major compounds, is highly toxic to colorectal cancer (CRC) cells. AFE induced cell cycle arrest at G1 phase and p21 and p27 genes, while those of CDK2, CDK-4, cyclin-D, and cyclin-E genes were downregulated in HCT116 cells. It predominantly induced apoptosis in HCT116p53+/+ cells while the HCT116p53-/- cells under the same treatment condition died by autophagy. Notably, AFE induced upregulation of AMPK phosphorylation, and inhibition of both of the mTOR complexes as indicated by inhibition of phosphorylation of S6K1, 4EBP1, and AKT. Furthermore, AFE inhibited mTOR-driven conversion of cells from reversible cell cycle arrest to senescence (geroconversion) as well as ERK activity. AFE activity was independent of ROS produced, and did not primarily target the cellular DNA or cytoskeleton. AFE also efficiently regressed CT26-derived solid tumor in Balb/c mice acting alone or in synergy with 5FU through inducing autophagy as a major mechanism of action as indicated by upregulation of Beclin 1 and phospho-AMPK, and inhibition of phospho-S6K1 levels in the tumor tissue lysates. CONCLUSION: AFE induced CRC death through activation of both apoptotic and autophagy pathways without affecting the normal cells. This study provided a logical basis for consideration of AFE in future therapy regimen to overcome the limitations associated with existing anti-CRC chemotherapy.

Andrographolide upregulates protein quality control mechanisms in cell and mouse through upregulation of mTORC1 function.

BACKGROUND: Heat shock response (HSR), a component of cellular protein quality control mechanisms, is defective in different neurodegenerative conditions such as Parkinson's disease (PD). Forced upregulation of heat shock factor 1 (HSF1), an HSR master regulator, showed therapeutic promise in PD models. Many of the reported small-molecule HSF1 activators have limited functions. Therefore, identification and understanding the molecular bases of action of new HSF1 activating molecules is necessary. METHOD: We used a cell-based reporter system to screen Andrographis paniculata leaf extract to isolate andrographolide as an inducer of HSF1 activity. The andrographolide activity was characterized by analyzing its role in different protein quality control mechanisms. RESULT: We find that besides ameliorating the PD in MPTP-treated mice, andrographolide upregulated different machineries controlled by HSF1 and NRF2 in both cell and mouse brain. Andrographolide achieves these functions through mTORC1 activated via p38 MAPK and ERK pathways. NRF2 activation is reflected in the upregulation of proteasome as well as autophagy pathways. We further show that NRF2 activation is mediated through mTORC1 driven phosphorylation of p62/sequestosome 1. Studies with different cell types suggested that andrographolide-mediated induction of ROS level underlies all these activities in agreement with the upregulation of mTORC1 and NRF2-antioxidant pathway in mice. CONCLUSION: Andrographolide through upregulating HSF1 activity ameliorates protein aggregation induced cellular toxicity. GENERAL SIGNIFICANCE: Our results provide a reasonable basis for use of andrographolide in the therapy regimen for the treatment of PD.