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.

Ovarian cancer is a serious cause of death in gynecological oncology. Delayed diagnosis and poor survival rates associated with late stages of the disease are major obstacles against treatment efforts. Heat shock proteins (HSPs) are stress responsive molecules known to be crucial in many cancer types including ovarian cancer. Clusterin (CLU), a unique chaperone protein with analogous oncogenic criteria to HSPs, has also been proven to confer resistance to anti-cancer drugs. Indeed, these chaperone molecules have been implicated in diagnosis, prognosis, metastasis and aggressiveness of various cancers. However, relative to other cancers, there is limited body of knowledge about the molecular roles of these chaperones in ovarian cancer. In the current review, we shed light on the diverse roles of HSPs as well as related chaperone proteins like CLU in the pathogenesis of ovarian cancer and elucidate their potential as effective drug targets.

https://www.mdpi.com/2072-6694/11/9/1389/pdf

Heat Shock Proteins and Ovarian Cancer: Important Roles and Therapeutic Opportunities

BackgroundBreast cancer is one of the leading cause of cancer-related deaths in women worldwide and increasing rapidly in developing countries. In the present study, we investigated the potential role and association of HSP70-2 with breast cancer.MethodsHSP70-2 expression was examined in 154 tumor and 103 adjacent non-cancerous tissue (ANCT) specimens and breast cancer cell lines (MCF7, BT-474, SK-BR-3 and MDA-MB-231) by RT-PCR, quantitative-PCR, immunohistochemistry, Western blotting, flow cytometry and indirect immunofluorescence. Plasmid driven short hairpin RNA approach was employed to validate the role of HSP70-2 in cellular proliferation, senescence, migration, invasion and tumor growth. Further, we studied the effect of HSP70-2 protein ablation on signaling cascades involved in apoptosis, cell cycle and Epithelial-Mesenchymal-Transition both in culture as well as in-vivo human breast xenograft mouse model.ResultsHSP70-2 expression was detected in majority of breast cancer patients (83 %) irrespective of various histotypes, stages and grades. HSP70-2 expression was also observed in all breast cancer cells (BT-474, MCF7, MDA-MB-231 and SK-BR-3) used in this study. Depletion of HSP70-2 in MDA-MB-231 and MCF7 cells resulted in a significant reduction in cellular growth, motility, onset of apoptosis, senescence, cell cycle arrest as well as reduction of tumor growth in the xenograft model. At molecular level, down-regulation of HSP70-2 resulted in reduced expression of cyclins, cyclin dependent kinases, anti-apoptotic molecules and mesenchymal markers and enhanced expression of CDK inhibitors, caspases, pro-apoptotic molecules and epithelial markers.ConclusionsHSP70-2 is over expressed in breast cancer patients and was involved in malignant properties of breast cancer. This suggests HSP70-2 may be potential candidate molecule for development of better breast cancer treatment.

Additional file 1: of Heat shock protein 70-2 (HSP70-2) overexpression in breast cancer

Coconut oil (CO) is enriched with medium chain saturated fatty acids like lauric acid (LA), capric acid and caprylic acid, which are known to have several health benefits. LA, the predominant fatty acid in CO, is reported to possess anticancer activity mediated through oxidative stress-induced apoptosis; however, there is no clear information on its cellular signalling mechanism. The present study screened the anticancer potential of various fatty acids present in CO (capric acid, caprylic acid and LA) using in silico tools such as CDOCKER in Accelrys Discovery Studio by targeting proteins like epidermal growth factor receptor (EGFR), cyclin-dependent kinase and thymidine synthase (TS). The results were further confirmed using cell culture-based studies and quantitative PCR. Among the tested compounds, LA was found to be the most active and showed a higher affinity towards EGFR and TS. Corroborating with these results, LA-induced dose-dependent cytotoxicity towards HCT-15 (human colon cancer), HepG2 (human hepatocellular carcinoma) and Raw 264.7 (murine macrophages) cells exhibiting morphological characteristics of apoptosis. Further, in HCT-15 cells exposed to LA (30 and 50 µg/mL), the expression of EGFR was found to be downregulated by 1.33- and 1.58-fold. The study thus concludes that the anticancer activity of LA may be partially mediated by the downregulation of EGFR signalling and consequent reduction in cell viability through apoptosis. Since EGFR signalling is crucial in cancer cell survival and is a prime target in drug development, the present study has pharmacological significance.

Lauric acid induce cell death in colon cancer cells mediated by the epidermal growth factor receptor downregulation: An in silico and in vitro study.

Tumour cell invasiveness is crucial for cancer metastasis and is not yet understood. Here we describe two functional screens for proteins required for the invasion of fibrosarcoma cells that identified the molecular chaperone heat shock protein 90 (hsp90). The hsp90a isoform, but not hsp90β, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90a decreases both MMP2 activity and invasiveness. This role for extracellular hsp90a in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.

Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness

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.

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

Virgin coconut oil (VCO) and turmeric are traditionally being used in Indian cuisine systems; VCO is a natural combination of medium-chain triglyceride and polyphenols with established pharmacologi...

Anusree Nair

Papers

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

Curcumin Enriched VCO Protects against 7,12-Dimethyl Benz[a] Anthracene-Induced Skin Papilloma in Mice