Phytochemicals as PI3K/ Akt/ mTOR Inhibitors and Their Role in Breast Cancer Treatment

Background:Breast cancer is the predominant form of cancer in women; various cellular pathways are involved in the initiation and progression of breast cancer. Among the various types of breast cancer that differ in their growth factor receptor status, PI3K/Akt signaling is a common pathway where all these converge. Thus, the PI3K signaling is of great interest as a target for breast cancer prevention; however, it is less explored.Objective:The present review is aimed to provide a concise outline of the role of PI3K/Akt/mTOR pathway in breast carcinogenesis and its progression events, including metastasis, drug resistance and stemness. The review emphasizes the role of natural and synthetic inhibitors of PI3K/Akt/m- TOR pathway in breast cancer prevention.Methods:The data were obtained from PubMed/Medline databases, Scopus and Google patent literature.Results:PI3K/Akt/mTOR signaling plays an important role in human breast carcinogenesis; it acts on the initiation and progression events associated with it. Numerous molecules have been isolated and identified as promising drug candidates by targeting the signaling pathway. Results from clinical studies confirm their application in the treatment of human breast cancer alone and in combination with classical chemotherapeutics as well as monoclonal antibodies.Conclusion:PI3K/mTOR signaling blockers have evolved as promising anticancer agents by interfering breast cancer development and progression at various stages. Natural products and bioactive components are emerging as novel inhibitors of PI3K signaling and more research in this area may yield numerous drug candidates.</jats:sec

Natural Products as PI3K/ Akt Inhibitors: Implications in Preventing Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the prominent forms of cancer in developed countries. Globally, the incidence of HCC is well correlated with fatty liver disease and cirrhosis; the underlying chronic inflammation and lipotoxicity are thought to drive the process of HCC. Several biochemical cycles and molecular pathways are associated. The review aims to summarize the role of PI3K/Akt signaling and its downstream effectors in the development of HCC and its progression. Further, the emphasis has been given to the role of natural inhibitors of the PI3K/Akt pathway in HCC prevention, which are under various levels of drug discovery. The required literature were collected from PubMed/Medline databases, as well as Scopus or Web of science. It is evident that various signaling pathways activated by growth factors together with detoxification machinery and biochemical cycles converge to the PI3K/Akt signaling. The pathway plays a key role in the carcinogenesis, metastasis and drug resistance events of HCC cells and provides the growth and survival advantage. Natural products belonging to various classes such as terpenoids, flavonoids, saponins and stilbenoids are proven inhibitors of PI3K signaling and also found to inhibit HCC progression. PI3K/mTOR pathway inhibitors, especially the different phytochemicals, emerged as promising as anti-HCC agents. These molecules are shown to interfere with the PI3K signaling at various stages and therefore the PI3K targeted drugs may be a future for the chemotherapeutic arena. </jats:sec

Pharmacological Potentials and Nutritional Values of Tropical and Subtropical Fruits of India: Emphasis on their Anticancer Bioactive Components

Background: Fruits are an important dietary component, which supply vitamins, minerals, as well as dietary fiber. In addition, they are rich sources of various biological and pharmacologically active compounds. Among these, temperate fruits are well studied for their pharmacological potentials, whereas tropical/subtropical fruits are less explored for their health impacts. In India, most of the consumed fruits are either tropical or subtropical. Objectives: The present review aims to provide a health impact of major tropical and sub-tropical fruits of India, emphasizing their anticancer efficacy. In addition, the identified bioactive components from these fruits exhibiting anticancer efficacy are also discussed along with the patent literature published. Methods: The literature was collected from various repositories, including NCBI, ScienceDirect, Eurekaselect, and Web of Science; literature from predatory journals was omitted during the process. Patent literature was collected from google patents and similar patent databases. Results: Tropical fruits are rich sources of various nutrients and bioactive components including polyphenols, flavonoids, anthocyanin, etc. By virtue of these biomolecules, tropical fruits have been shown to interfere with various steps in carcinogenesis, metastasis, and drug resistance. Their mode of action is either by activation of apoptosis, regulation of cell cycle, inhibition of cell survival and proliferation pathways, increased lipid trafficking or inhibiting inflammatory pathways. Several molecules and combinations have been patented for their anticancer and chemoprotective properties. Conclusion: Overall, the present concludes that Indian tropical/ subtropical fruits are nutritionally and pharmacologically active and may serve as a source of novel anticancer agents in the future. </jats:sec

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

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. </jats:sec

Inhibitory Potential of Dietary Nutraceuticals on Cellular PI3K/Akt Signaling: Implications in Cancer Prevention and Therapy

Background: The phosphatidyl inositol-3 kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling has been associated with many cellular physiological events, such as proliferation, maturation, survival, and metabolism. Besides its role in normal cells, the pathway is often upregulated in various cancers. Due to its prominent role in the cancer progression events, it is now being considered as a target for cancer therapy and cancer chemoprevention. Objectives: The present review provides a concise outline of the role of the PI3K/Akt/mTOR pathway in carcinogenesis and progression events, including metastasis, drug resistance and stemness. Further, emphasis needs to be placed on the PI3K/Akt/mTOR pathway inhibitory potentials of various food-derived bioactive components in cancer prevention. Methods: Data on the PI3K/Akt/mTOR inhibiting natural products and their bioactive compounds have been obtained from PubMed/Medline, Scopus, Eurekaselect, etc. Findings from the above citation databases from 2000-2021 are included in the manuscript. Results: Numerous compounds from plants have been isolated and identified as anticancer agents; among these, a predominant class is nutraceuticals. The PI3K pathway is the predominant target of these natural products, and many of these drug candidates are under various stages of drug development. These compounds have shown a significant inhibitory effect on the kinase activities of PI3K and Akt, resulting in the abrogation of cancer initiation and progression events. In addition, these compounds have been shown to reverse the resistance to chemotherapeutic drugs and also reduce the population of cancer stem cells. Conclusion: The nutraceuticals are promising candidates as anticancer agents by blocking PI3K signaling cascades. As the PI3K is a central pathway to various receptors signaling, the dietary intervention may prove to be highly effective. </jats:sec

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

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.</jats:sec

Bacterioplankton diversity and pollution levels in the estuarine regions of Chaliyar and Anjarakkandi rivers, Kerala, India

AbstractRivers and the estuarine regions play crucial roles in the environment by controlling the nutrient cycling, waste disposal, and also in supporting biodiversity. However, the estuarine regions of rivers are highly susceptible to disruptive changes by anthropogenic pollutants and eutrophication. Bacterioplankton diversity is the best indicators of the pollution level and eutrophication status of the rivers. The present study evaluated the eutrophication status and bacterioplankton diversity of the estuarine regions of Chaliyar and the Anjarakkandi originated from the Western Ghats. The present study observed the presence of increased incidence of bacterioplankton comprising of proteobacteria, actinobacteria and cyanobacteria in the estuarine regions of Anjarakkandi river compared to that of Chaliyar river. Further, the percentage incidence of faecal bacteria including Bacillus subtilis and E. coli, were also found to be in high in the Anjarakkandi river; in corroborating with this, the diversity of nitrogen metabolizing bacteria was also higher in the estuarine samples of Anjarakkandi river. Corroborating with this, the levels of water nutrients including nirates, nitrites and phosphates were high in the Anjarakkandi compared to the Chaliyar river. Together, it is possible that there might be increased faecal contamination and subsequent increased eutrophication in the estuarine regions of Anjarakkandi river. Altogether, the study concludes that the Anjarakkandi river may be more polluted and which is partly contributed by faecal contaminants and also responsible for the change in the bacterioplankton community of the estuaries.</jats:p

Natural Bioactive Compounds and Human Health

Natural bioactive compounds encompass a vast array of molecules derived from plants, fungi, marine organisms, and other natural sources [...