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      Potential of Zerumbone as an Anti-Cancer Agent

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          Abstract

          Cancer is still a major risk factor to public health globally, causing approximately 9.8 million deaths worldwide in 2018. Despite advances in conventional treatment modalities for cancer treatment, there are still few effective therapies available due to the lack of selectivity, adverse side effects, non-specific toxicities, and tumour recurrence. Therefore, there is an immediate need for essential alternative therapeutics, which can prove to be beneficial and safe against cancer. Various phytochemicals from natural sources have been found to exhibit beneficial medicinal properties against various human diseases. Zerumbone is one such compound isolated from Zingiber zerumbet Smith that possesses diverse pharmacological properties including those of antioxidant, antibacterial, antipyretic, anti-inflammatory, immunomodulatory, as well as anti-neoplastic. Zerumbone has shown its anti-cancer effects by causing significant suppression of proliferation, survival, angiogenesis, invasion, and metastasis through the molecular modulation of different pathways such as NF-κB, Akt, and IL-6/JAK2/STAT3 (interleukin-6/janus kinase-2/signal transducer and activator of transcription 3) and their downstream target proteins. The current review briefly summarizes the modes of action and therapeutic potential of zerumbone against various cancers.

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          Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals.

          Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed "Let food be thy medicine and medicine be thy food." Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, gamma-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed.
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            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.
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              Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer.

              Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis. The leakiness in the tumor microvasculature is attributed to the tumor cells migrating to distal site organs and forming colonies.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                18 February 2019
                February 2019
                : 24
                : 4
                : 734
                Affiliations
                [1 ]Cancer Biology Laboratory, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology, Guwahati, Assam 781039, India; sosmi176106101@ 123456iitg.ac.in (S.G.); bano176106104@ 123456iitg.ac.in (B.S.); j.monisha@ 123456iitg.ernet.in (J.M.)
                [2 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; phcfanl@ 123456nus.edu.sg (L.F.); phsceh@ 123456nus.edu.sg (C.E.H.)
                [3 ]Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; frank.arfuso@ 123456curtin.edu.au
                [4 ]College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
                Author notes
                [* ]Correspondence: ksahn@ 123456khu.ac.kr (K.S.A.); phcgs@ 123456nus.edu.sg (G.S.); kunnumakkara@ 123456iitg.ac.in or ajai78@ 123456gmail.com (A.B.K.); Tel.: +82-2-961-2316 (K.S.A.); +65-6516-3267 (G.S.); +91-361-258-2231 (A.B.K.); Fax: +65-6873-7690 (G.S.); +91-361-258-2249 (A.B.K.)
                Author information
                https://orcid.org/0000-0001-7678-9472
                https://orcid.org/0000-0002-2882-0612
                Article
                molecules-24-00734
                10.3390/molecules24040734
                6413012
                30781671
                26e58ec2-1b7e-41eb-9281-d1382fd53823
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 December 2018
                : 16 February 2019
                Categories
                Review

                zerumbone,cancer,apoptosis,nf-κb,il-6/jak2/stat3,akt,foxo1
                zerumbone, cancer, apoptosis, nf-κb, il-6/jak2/stat3, akt, foxo1

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