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Principal Investigator: Lorne J Hofseth
Organization: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
Fiscal Year: 2024
Award: $323,796
Funding agency: National Cancer Institute
PROJECT SUMMARY
Affecting upwards of 4 million people in North America and Europe, with an economic burden of $30 -
$45 billion, Inflammatory Bowel Diseases (IBDs) are debilitating, significantly affect life-style, and carry a high
colon cancer risk. Because conventional treatment outcomes are modest with dangerous side effects, about half
of IBD patients turn to complementary and alternative medicines (CAMs). Although CAMs have been used for
thousands of years, there is a gap in our knowledge of the mechanisms supporting their effectiveness.
Understanding these mechanisms will lead to standardized treatment for IBD outside of toxic FDA-approved
drugs. This will lower their colon cancer risk. Over the past decade, we have shown that American Ginseng (AG)
suppresses colitis and prevents colon cancer in mice. Using scientifically rigorous Bioassay-Guided
Fractionation, we have isolated a polyacetylene called panaxynol (PA) that has anti-inflammatory and anti-cancer
properties. PA (compared to the100's of other CAMs being tested) comes from a natural source, and is a single
ingredient, allowing it to be standardized on its own, or in a cocktail. What makes this molecule particularly
interesting and innovative is the mechanism - it is a single molecule extracted from AG, with a unique capacity
to target macrophages (mΦ) for apoptosis. Our long-term goal is to identify the primary component(s) of AG
responsible for the robust anti-inflammatory and chemopreventive properties of AG we have observed over the
past decade; and to determine their mechanism of action. The overall objective of this application is to gain a
deeper understanding of both: (a) the broad treatment potential of PA (i.e. multiple pharmacologic and
bioengineered animal models of colitis and colon cancer); and (b) the underlying mechanism(s) behind the
observation that PA targets mΦ for apoptosis. We focus here on a DNA-damage independent p53 signaling
pathway as a mechanism toward mΦ apoptosis. The scientific premise underlying the proposed research is
robust. Comparing nine FDA-approved drugs, small molecules, and CAMs, PA is the most efficacious at
suppressing colitis in a DSS mouse model. Our central hypothesis is that PA, isolated after a decade of rigorous
bioassay-guided fractionation, has anti-inflammatory and anti-cancer activity in the colon because it activates
p53- mediated apoptosis in infiltrating mΦ; mitigating colitis; and preventing colon cancer associated with colitis.
Furthermore, PA acts as an anti-inflammatory in these models because it induces p53 through a DNA damage-
like signaling response in mΦ that is independent of detectable DNA damage. To address this hypothesis, we
will test the efficacy of PA in three mouse models of colitis and in genetically engineered mice. Because it
appears that PA is taking advantage of a unique p53 mechanism in mΦ, we will test PA in mice with p53
conditionally knocked out in colonic mΦ. A DNA damage-independent mechanism is explored. Results
consistent with our hypothesis would identify an innovative, low cost, safe, specific, and natural compound with
anti-inflammatory and cancer chemopreventive properties that could quickly be implemented clinically.
Terms: <(TNF)-α><Ablation><Address><Affect><American><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antioncogene Protein p53><Apoptosis><Apoptosis Pathway><Area><Assay><Autoimmune Diseases><Bioassay><Biological Assay><Biomedical Engineering><Cachectin><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Tumor Antigen P53><Chemical Fractionation><Chemicals><Chemoprevention><Chemopreventive><Chemopreventive Agent><Clinical><Clinical Trials><Co-culture><Cocultivation><Coculture><Coculture Techniques><Colitis><Colon><Colon Cancer><Colon Carcinoma><Combined Modality Therapy><Complementary and alternative medicine><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><DNA><DNA Damage><DNA Injury><DSS colitis><DSS model><DSS mouse model><DSS-induced acute colitis><DSS-induced colitis><Dangerousness><Deoxyribonucleic Acid><Disease><Disorder><Dose><Drug Kinetics><Drugs><Dysfunction><Economic Burden><Effectiveness><Europe><Exposure to><FDA approved><FRACN><Fractionation><Fractionation Radiotherapy><Functional disorder><GEM model><GEMM model><Genetically Engineered Mouse><Genome><Ginseng><Ginseng Preparation><Goals><Granulomatous Enteritis><Immune><Immunes><Induction of Apoptosis><Infiltration><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intestinal><Intestines><Intracellular Communication and Signaling><Knowledge><Lead><Life Style><Lifestyle><LoxP-flanked allele><Macrophage><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Mice><Mice Mammals><Modeling><Molecular><Monocyte-Derived TNF><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myeloid Cells><Mφ><Natural Compound><Natural Source><Nature><North America><Oncoprotein p53><P53><Pathway interactions><Patients><Pb element><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phosphoprotein P53><Phosphoprotein pp53><Physiopathology><Plants><Prevalence><Programmed Cell Death><Property><Protein TP53><Research><Resveratrol><SIRT1><SIRT1 gene><Sepsis><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sirtuin 1><Standardization><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TP53><TP53 gene><TRP53><Testing><Toxic effect><Toxicities><Treatment outcome><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor Protein p53><Tumor Protein p53 Gene><Ulcerated Colitis><Ulcerative Colitis><anti-cancer><anti-carcinogenic><anticancer activity><anticarcinogenic><autoimmune condition><autoimmune disorder><autoimmunity disease><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><blood infection><bloodstream infection><bowel><cancer chemoprevention><cancer in the colon><cell type><cellular targeting><chemoprevention agent><colitis mouse model><colitis murine model><colitis-induced dysbiosis><colon cancer prevention><colon cancer risk><combination therapy><combined modality treatment><combined treatment><conditional knock-out><conditional knockout><conventional therapy><conventional treatment><cost><dextran sulfate sodium colitis><dextran sulfate sodium induced colitis><dextran sulfate sodium model><dextran sulfate sodium mouse model><drug/agent><efficacy testing><eleocolitis><experiment><experimental research><experimental study><experiments><floxed><floxed allele><genetically engineered mouse model><genetically engineered murine model><heavy metal Pb><heavy metal lead><improved><in vivo><inflammatory disease of the intestine><inflammatory disorder of the intestine><innovate><innovation><innovative><intestinal autoinflammation><malignancy><microbial consortia><microbial flora><microbiota><microflora><model of animal><mouse colitis><multi-modal therapy><multi-modal treatment><multispecies consortia><murine colitis><naturally occurring compound><neoplasm/cancer><novel><p53 Antigen><p53 Genes><p53 Signaling Pathway><p53 Tumor Suppressor><pathophysiology><pathway><pharmacologic><prevent colon cancer><protein p53><regional enteritis><replication stress><response><sex><side effect><single molecule><small molecule><sound><treatment strategy>