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      Novel Marine Phenazines as Potential Cancer Chemopreventive and Anti-Inflammatory Agents

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          Abstract

          Two new ( 1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC 50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC 50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE 2 production was blocked with greater efficacy (IC 50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects.

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          Inflammation and cancer: how hot is the link?

          Bharat B. Aggarwal, Shishir Shishodia, Santosh K. Sandur … (2006)
          Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-kappaB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and gamma-irradiation. These observations imply that anti-inflammatory agents that suppress NF-kappaB or NF-kappaB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer.
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            iNOS-mediated nitric oxide production and its regulation.

            Fugen Aktan (2004)
            This review focuses on the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and its regulation under physiological and pathophysiological conditions. NO is an important biological mediator in the living organism that is synthesized from L-arginine using NADPH and molecular oxygen. However, the overproduction of NO which is catalyzed by iNOS, a soluble enzyme and active in its dimeric form, is cytotoxic. Immunostimulating cytokines or bacterial pathogens activate iNOS and generate high concentrations of NO through the activation of inducible nuclear factors, including NFkB. iNOS activation is regulated mainly at the transcriptional level, but also at posttranscriptional, translational and postranslational levels through effects on protein stability, dimerization, phosphorylation, cofactor binding and availability of oxygen and L-arginine as substrates. The prevention of the overproduction of NO in the living organism through control of regulatory pathways may assist in the treatment of high NO-mediated disorders without changing physiological levels of NO. Copyright 2004 Elsevier Inc.
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              Inflammation: gearing the journey to cancer.

              Joydeb Kundu, Young-Joon Surh (2008)
              Chronic inflammation plays a multifaceted role in carcinogenesis. Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis, etc. Inflammation-induced reactive oxygen and nitrogen species cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. Overexpression, elevated secretion, or abnormal activation of proinflammatory mediators, such as cytokines, chemokines, cyclooxygenase-2, prostaglandins, inducible nitric oxide synthase, and nitric oxide, and a distinct network of intracellular signaling molecules including upstream kinases and transcription factors facilitate tumor promotion and progression. While inflammation promotes development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Many of proinflammatory mediators, especially cytokines, chemokines and prostaglandins, turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will end up with tumor angiogenesis, metastasis and invasion. Moreover, cellular microRNAs are emerging as a potential link between inflammation and cancer. The present article highlights the role of various proinflammatory mediators in carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mar Drugs
                Journal ID (publisher-id): marinedrugs
                Title: Marine Drugs
                Publisher: MDPI
                ISSN (Electronic): 1660-3397
                Publication date (Electronic): 16 February 2012
                Publication date Collection: February 2012
                Volume: 10
                Issue: 2
                Pages: 451-464
                Affiliations
                [1 ]College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA; Email: kondraty@ 123456hawaii.edu (T.P.K.); eunjungp@ 123456hawaii.edu (E.-J.P.)
                [2 ]Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA; Email: ryu9@ 123456uic.edu (R.Y.); breemen@ 123456uic.edu (R.B.B.); btmurphy@ 123456uic.edu (B.T.M.)
                [3 ]Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, CA 92093, USA; Email: rasolkar@ 123456marronebio.com (R.N.A.); wfenical@ 123456ucsd.edu (W.F.)
                Author notes
                [* ]Author to whom correspondence should be addressed; Email: pezzuto@ 123456hawaii.edu ; Tel.: +1-808-933-2909; Fax: +1-808-933-2981.
                Article
                Publisher ID: marinedrugs-10-00451
                DOI: 10.3390/md10020451
                PMC ID: 3297008
                PubMed ID: 22412812
                SO-VID: 3885a58a-8156-4327-bed6-c54e3dd48d71
                Copyright © © 2012 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 27 December 2011
                Date revision received : 08 February 2012
                Date accepted : 13 February 2012
                Categories
                Subject: Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: lavanducyanin ,inflammation,phenazines,chemoprevention,nfκb,apoptosis
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: lavanducyanin , inflammation, phenazines, chemoprevention, nfκb, apoptosis

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