Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.

Atorvastatin inhibited Rho-associated kinase 1 (ROCK1) and focal adhesion kinase (FAK) mediated adhesion and differentiation of CD133+CD44+ prostate cancer stem cells.

Prostate cancer has become a global health concern and is one of the leading causes of cancer death of men after lung and gastric cancers. It has been suggested that the 3-hydroxy-3-methyl-glutarylcoenzyme-CoA (HMG-CoA) reductase inhibitor atorvastatin shows anticancer activity in prostate cancer cell lines. To this end, we analyzed the influence of atorvastatin on the cell adhesion and differentiation of CD133(+)CD44(+) cells derived from prostate cancer biopsies and peripheral blood. CD133(+)CD44(+) cells were treated with atorvastatin (16-64µM) for different time periods. Cell adhesion to endothelial cell monolayers and differentiation into prostate cancer cells were evaluated. α1, ß1 and α2ß1 integrins adhesion receptors and the downstream target of atorvastatin Rho-dependent kinase (ROCK) and focal adhesion kinase (FAK) were analyzed by Western blot. Further blocking studies with the ROCK inhibitor H1152, anti-FAK antibody and anti-integrin α1 and ß1 antibodies were carried out. Atorvastatin treatment inhibited dose-dependently cell attachment to endothelium and differentiation. The inhibitory effect of atorvastatin on cell adhesion was associated with decreased expression of integrins α1 and ß1 and phosphorylated MYPT1 and FAK. Furthermore, atorvastatin strongly reduced ROCK1 and FAK mediated differentiation of CD133(+)CD44(+) cells, which was confirmed by antibody treatment. Atorvastatin modified the expression of cell adhesion molecules and differentiation markers. These beneficial effects of atorvastatin may be mediated by ROCK and FAK signaling pathway. The data presented may point to novel treatment options for prostate cancer.

Phospholipase A2 Isoforms as Novel Targets for Prevention and Treatment of Inflammatory and Oncologic Diseases.

Phospholipase A2s (PLA2s) are group of enzymes, which cleave phospholipids specifically at sn-2 position to liberate free fatty acid, mostly arachidonic acid (AA) and lysophospholipids (LPLs). Inhibition of PLA2 prevents the liberation of AA and LPLs. Hence, researchers have been considering PLA2s could be a better therapeutic target than the downstream enzymes cyclooxygense and lipoxygenase. Several isoforms of PLA2s exist; they are mainly divided into secretory PLA2s (sPLA2), cytosolic PLA2s (cPLA2), and calcium independent PLA2s (iPLA2), platelet activating factor- acyl hydrolase (PAF-AH), lysosomal PLA2 (LPLA2), adipose-specific PLA2 (Ad- PLA). Each isoform of PLA2s is different in its chemical structure and physiological functions. sPLA2s (Groups IIA, V and X) are well characterized as proinflammatory mediating enzymes but their role in cancer is controversial. Groups IVA, IVB and IVC cPLA2s are present in humans but only Group IVA cPLA2 plays key role in pathophysiology of various cancers and inflammation. The role of iPLA2 in inflammation and cancer is limited. Lipoprotein associated PLA2 (Group VIIA PLA2), a PAF-AH isoform, has key role in atherosclerosis. Several isoform specific PLA2 inhibitors have been developed and some of the PLA2s inhibitors are currently under clinical trials for various inflammatory and oncologic diseases. This review focuses on the recent experimental evidences to support the notion that PLA2s are causally implicated in the pathobiology of cancer and inflammatory related disorders and discuss the potential utility of isoform specific PLA2 inhibitors as preventive and/or therapeutic agents.

Therapeutic Potentials of Triterpenes in Diabetes and its Associated Complications.

Diabetes is a major chronic metabolic disorder globally and around of 285 million people are affected by the disease and the number is expected to double in the next two decades. The major focus of anti-diabetic therapies is to enhance insulin production, sensitivity and/or reduce the blood glucose level. Although several synthetic drugs have been developed as antidiabetic agents but their utility has been hampered due to their side effects and poor efficacy. In this scenario, research on natural products has been gained importance due their safety profile in toxicity studies. Terpenoids belong to an important class of natural products and several terpenoids have been reported as antidiabetic agents. Some of them are under various stages of pre-clinical and clinical evaluation to develop them as antidiabetic agents. These agents can inhibit enzymes responsible for the development of insulin resistance, normalization of plasma glucose and insulin levels and glucose metabolism. Triterpenes can act as promising agents in the treatment of diabetic retinopathy, neuropathy and nephropathy or in impaired wound healing by inhibiting several pathways involved in the diabetes and associated complications. However, efforts in understanding the biological actions and clinical studies involving the applications of triterpenes in treating diabetes are very limited. Hence, special attention is imperative to explore the therapeutic potential of these compounds and provide new information to the scientific community. This review aims to provide the recent advances in triterpenes chemistry, its derivatives, biological interventions and its therapeutic applications with special emphasis on diabetes and its associated disorders.

Docking studies of Vitamin C, Vitamin E, Damnacanthal and Scopoletin with human lens gamma D-crystalline.

Vitamin C, Vitamin E, scopoletin and damnacanthal are the major constituents of Noni (Morinda citrifolia). These compounds are known to have good medicinal properties and they are known to act as antioxidants. Loss of vision in elderly is due to opaqueness of the lens proteins such as gamma-D-crystallin during oxidative stress conditions. Therefore, it is of importance to find the potential interaction of Vitamin C, Vitamin E, Scopoletin and Damnacanthal with the lens protein gamma-D-crystallin. Hence, their physical binding to gamma-D crystallin (PDB ID: 2G98) was evaluated using molecular and structural docking procedures. Results show the potential binding of all the above anti-oxidants to gamma-D-crystalline with equal affinity. Thus, the role of cumulative anti-oxidant effect in Noni fruit juice through their potential yet predicted interaction with the lens protein gamma-D-crystallin is implied for cataract treatment.