Background Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence.

Background The potential applications of food-derived antioxidant peptides as additives, nutraceuticals and therapeutic agents have fueled current interests to discover them from diverse plant sources. A growing number of antioxidant peptides have been identified from edible plant sources, as well as plant-based agricultural and food-processing by-products. Scope and approach We summarized recent progress in the research of plant-derived antioxidant peptides, particularly their biological effects, mechanisms, and structure-activity relationship. Many studies assessed the potency of antioxidant peptides by using chemical assays. However, the outcome of chemical methods may not reflect the biological significance. Thus, this review focusses on antioxidant peptides whose effectiveness was demonstrated by using cellular and/or animal models. This review pays particular attention to studies which successfully determined the sequences of antioxidant peptides under investigation. Due to the scarcity of the assessment of pure antioxidant peptides in animal models, in vivo evidence from well-characterized peptide fractions or hydrolysates will also be discussed. Key findings and conclusions Plant-derived antioxidant peptides diminished reactive oxygen species production, besides activating endogenous antioxidant defenses in cellular models. Some such peptides exerted protection by modulating pro- and anti-apoptotic proteins as well as gene and protein expression of antioxidant enzymes. By using cellular models, the intestinal absorption and metabolism of such peptides were elucidated. Plant protein hydrolysates enhanced antioxidant protection in animal models, often by upregulating antioxidant enzyme activities in various body tissues. The structure-activity relationship of plant-derived antioxidant peptides is not well-understood. Nevertheless, information connecting peptide secondary structure to cellular antioxidant effects has emerged.

Advances on the antioxidant peptides from edible plant sources

As a plasticizer, di(2-ethylhexyl) phthalate (DEHP) is the most usually used phthalate. Leydig cell is a male-specific cell, which plays a principal role in spermatogenesis and masculinization by the androgens of synthesis and secretion. Numerous researchers have indicated that DEHP can result in testicular toxicity by inducing oxidative stress. Lycopene (LYC) is a possible treatment option for male infertility due to its natural antioxidant properties. Our study was aimed to investigate whether LYC could rescue DEHP-induced Leydig cell damage. The mice were treated with DEHP (500 mg/kg BW/day or 1000 mg/kg BW/day) and/or LYC (5 mg/kg BW/day) for 28 days. We found that LYC attenuated DEHP-induced Leydig cell damage. Moreover, the protective role of LYC was verified by the histopathological and ultrastructural analysis of the Leydig cell. LYC suppressed oxidative stress that was induced by DEHP. In the Leydig cell, the expressions of the nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target genes were improved through LYC-mediated protection in DEHP-induced Leydig cell damage. Our findings indicated that LYC could increase the antioxidant capacity via mediating Nrf2 signaling pathway, thereby attenuating DEHP-induced Leydig cell damage.

Lycopene Prevents DEHP-Induced Leydig Cell Damage with the Nrf2 Antioxidant Signaling Pathway in Mice

Biocatalytic and Antioxidant Nanostructures for ROS Scavenging and Biotherapeutics

Radiosensitizers are agents capable of amplifying injury to tumor tissues by enhancing DNA damage and fortifying production of radical oxygen species (ROS). The use of such radiosensitizers in the clinic, however, remains limited by an insufficient ability to differentiate between cancer and normal cells and by the presence of a reversible glutathione system that can diminish the amount of ROS generated. Here, to address these limitations, we design an H2O2-responsive prodrug which can be premixed with lauric acid (melting point ∼43 °C) and loaded around the surface of silica-coated bismuth nanoparticles (BSNPs) for cancer-specific photoradiotherapy. Particularly, silica coating confers BSNPs with improved chemical stability against both near-infrared light and X-rays. Upon photothermal heating, lauric acid is melted to trigger prodrug release, followed by its transformation into p-quinone methide via H2O2 stimulation to irreversibly alkylate glutathione. Concurrently, this heat boosts tumor oxygenation and helps relieve the hypoxic microenvironment. Following sequential irradiation by X-rays, BSNPs generate plentiful ROS, which act in combination with these events to synergistically induce cell death via DNA breakage and mitochondria-mediated apoptosis pathways, ultimately enabling effective inhibition of tumor growth in vivo with high tumor specificity and reduced side effects. Collectively, this work presents a promising approach for the improvement of other ROS-responsive proalkylating agents, while simultaneously highlighting a robust nanosystem for combining these prodrugs with photoradiosensitizers to realize precision photoradiotherapy.

Highly Stable Silica-Coated Bismuth Nanoparticles Deliver Tumor Microenvironment-Responsive Prodrugs to Enhance Tumor-Specific Photoradiotherapy.

Glutathione (GSH or reduced glutathione) is a tripeptide of gamma-Glutamyl-cysteinylglycine and the predominant intracellular antioxidant in many organisms including humans. GSH and associated enzymes are controlled by a transcription factor-nuclear factor-2 related erythroid factor-2 (Nrf2). In cellular milieu, GSH protects the cells essentially against a wide variety of free radicals including reactive oxygen species, lipid hydroperoxides, xenobiotic toxicants, and heavy metals. It has two forms, the reduced form or reduced glutathione (GSH) and oxidized form (GSSG), where two GSH moieties combine by sulfhydryl bonds. Glutathione peroxidase (GPx) and glutathione-s-transferase (GST) essentially perform the detoxification reactions using GSH, converting it into GSSG. Glutathione reductase (GR) operates the salvage pathway by converting GSSG to GSH with the expense of NADPH and restores the cellular GSH pool. Hence, GSH and GSH-dependent enzymes are necessary for maintaining the normal redox balance in the body and help in cell survival under stress conditions. In addition, GST removes various carcinogenic compounds offering a chemopreventive property, whereas the GSH system plays a significant role in regulating the cellular survival by offering redox stability in a variety of cancers including prostate, lung, breast, and colon cancer. Studies have also indicated that GSH inhibitors, such as buthionine sulfoximine, improve the chemo-sensitivity in cancer cells. In addition, GSH and dependent enzymes provide a survival advantage for cancer cells against chemotherapeutic drugs and radiotherapy.

Glutathione, an Antioxidant Tripeptide: Dual Roles in Carcinogenesis and Chemoprevention

Background Heat shock proteins (HSPs) are predominant molecular chaperones which are actively involved in the protein folding; which is essential in protecting the structure and functioning of proteins during various stress conditions. Though HSPs have important physiological roles, they have been well known for their roles in various pathogenic conditions such as carcinogenesis; however, limited literature has consolidated its potential as an anti-metastatic drug target. Objectives The present review outlines the role of different HSPs on cancer progression and metastasis; possible role of HSP inhibitors as anti-neoplastic agents is also discussed. Methods The data were collected from PubMed/Medline and other reputed journal databases. The literature that was too old and had no significant role to the review was then omitted. Results Despite their strong physiological functions, HSPs are considered as good markers for cancer prognosis and diagnosis. They have control over survival, proliferation and progression events of cancer including drug resistance, metastasis, and angiogenesis. Since, neoplastic cells are more dependent on HSPs for survival and proliferation, the selectivity and specificity of HSP-targeted cancer drugs remain high. This has made various HSPs potential clinical and experimental targets for cancer prevention. An array of HSP inhibitors has been in trials and many others are in experimental conditions as anticancer and anti-metastatic agents. Several natural products are also being investigated for their efficacy for anticancer and anti-metastatic agents by modulating HSPs. Conclusion Apart from their role as an anticancer drug target, HSPs have shown to be promising targets for the prevention of cancer progression. Extensive studies are required for the use of these molecules as anti-metastatic agents. Further studies in this line may yield specific and effective antimetastatic agents.

Vinayak Narayanankutty

Papers

Glutathione, an Antioxidant Tripeptide: Dual Roles in Carcinogenesis and Chemoprevention

Heat Shock Proteins (HSPs): A Novel Target for Cancer Metastasis Prevention