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Yarla N.S.,Gandhi Institute of Technology and Management | Bishayee A.,Larkin Health science Institute | Sethi G.,National University of Singapore | Sethi G.,Curtin University Australia | And 8 more authors.
Seminars in Cancer Biology | Year: 2016

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. © 2016 Elsevier Ltd. Source

Sinha D.,Chittaranjan National Cancer Institute | Sarkar N.,Chittaranjan National Cancer Institute | Biswas J.,Chittaranjan National Cancer Institute | Bishayee A.,Larkin Health science Institute
Seminars in Cancer Biology | Year: 2016

Globally, breast cancer is the most frequently diagnosed cancer among women. The major unresolved problems with metastatic breast cancer is recurrence after receiving objective response to chemotherapy, drug-induced side effects of first line chemotherapy and delayed response to second line of treatment. Unfortunately, very few options are available as third line treatment. It is clear that under such circumstances there is an urgent need for new and effective drugs. Phytochemicals are among the most promising chemopreventive treatment options for the management of cancer. Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a non-flavonoid polyphenol present in several dietary sources, including grapes, berries, soy beans, pomegranate and peanuts, has been shown to possess a wide range of health benefits through its effect on a plethora of molecular targets.The present review encompasses the role of resveratrol and its natural/synthetic analogue in the light of their efficacy against tumor cell proliferation, metastasis, epigenetic alterations and for induction of apoptosis as well as sensitization toward chemotherapeutic drugs in various in vitro and in vivo models of breast cancer. The roles of resveratrol as a phytoestrogen, an aromatase inhibitor and in stem cell therapy as well as adjuvent treatment are also discussed. This review explores the full potential of resveratrol in breast cancer prevention and treatment with current limitations, challenges and future directions of research. © 2016 Elsevier Ltd. Source

Bishayee A.,Larkin Health science Institute | Block K.,Block Center for Integrative Cancer Treatment
Seminars in Cancer Biology | Year: 2015

Despite exciting advances in targeted therapies, high drug costs, marginal therapeutic benefits and notable toxicities are concerning aspects of today's cancer treatments. This special issue of Seminars in Cancer Biology proposes a broad-spectrum, integrative therapeutic model to complement targeted therapies. Based on extensive reviews of the cancer hallmarks, this model selects multiple high-priority targets for each hallmark, to be approached with combinations of low-toxicity, low-cost therapeutics, including phytochemicals, adapted to the well-known complexity and heterogeneity of malignancy. A global consortium of researchers has been assembled to advance this concept, which is especially relevant in an era of rapidly expanding capacity for genomic tumor analyses, alongside alarming growth in cancer morbidity and mortality in low- and middle-income nations. © 2015 Elsevier Ltd. Source

Sinha D.,Chittaranjan National Cancer Institute | Dutta K.,Chittaranjan National Cancer Institute | Ganguly K.K.,Chittaranjan National Cancer Institute | Biswas J.,Chittaranjan National Cancer Institute | And 2 more authors.
Molecular Carcinogenesis | Year: 2015

A methyl derivative natural triterpenoid amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) has been found to possess antiproliferative, proapoptotic, and antiinflammatory effects against established tumor cells. Large-scale synthesis of pure AMR-Me has eliminated the need of the natural phytochemical for further development of AMR-Me as an anticancer drug. Metastatic melanoma is a fatal form of cutaneous malignancy with poor prognosis and limited therapeutic options. It was hypothesized that antitumor pharmacological effect of AMR-Me could be linked to AMR-Me-mediated suppression of the metastatic potential of B16F10 murine melanoma. AMR-Me was assessed for its antimetastatic efficacy by cell adhesion, migration, and invasion assays in B16F10 cells. The signaling crosstalk was explored by gelatin zymography, Western blot, ELISA, and immunocytochemistry. The results elicited that AMR-Me was successful in restricting the adhesion, migration, and invasion of highly metastatic cells. The antimetastatic potential of this compound may be attributed to the reduced expression of membrane type 1 metalloproteinase (MT1-MMP) and matrix metalloproteinases (MMP-2 and MMP-9). AMR-Me was found to downregulate vascular endothelial growth factor (VEGF)/phosphorylated forms of focal adhesion kinase (pFAK397)/Jun N-terminus kinase (pJNK)/extracellular signal-regulated kinase (pERK). This, in turn, inhibited transcription factor nuclear factor-κB (NF-κB) and transactivation of MMPs. Moreover, the activation of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) might have influenced the downmodulation of MT1-MMP, MMP-2, and MMP-9. AMR-Me suppresses the activity of MT1-MMP, MMP-2, and MMP-9 by downregulation of VEGF/pFAK397/pJNK/pERK/NF-κB and activation of TIMP-1 and TIMP-2 in metastatic melanoma cell line, B16F10. AMR-Me has the potential as an effective anticancer drug for metastatic melanoma which is a dismal disease. © 2014 Wiley Periodicals, Inc. Source

Jia L.Y.,National University of Singapore | Shanmugam M.K.,National University of Singapore | Sethi G.,National University of Singapore | Sethi G.,Curtin University Australia | Bishayee A.,Larkin Health science Institute
Anti-Cancer Drugs | Year: 2016

Breast cancer is the most common cancer type that affects women and is the major cause of morbidity and mortality. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype and accounts for 10-20% of all breast cancer cases. TNBC is commonly characterized by the absence of estrogen, progesterone, and the Her2/neu receptor and is usually diagnosed by immunohistochemistry. Mutations in the BRCA1 gene, as well as overexpression of oncogenic kinases, such as human epidermal growth factor receptor 2, vascular endothelial growth factor-A, insulin-like growth factor-1 (IGF-1)/IGF-1 receptor, and transforming growth factor-β1, have been found to be correlated with a higher risk of metastasis and poor overall survival in TNBC patients. The current review briefly discusses the various treatment options including chemotherapeutics and targeted therapies that are available currently for the therapy of TNBC patients and highlights their comparative benefits and disadvantages for clinical application. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

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