Progress 12/01/15 to 05/31/19
Outputs
Target Audience:Over the course of the entire project period (12/1/2015-5/31/2019) we have reached out to multiple target audiences in order to: 1) disseminate our scientific findings, and 2)initiate the process of translating this research into a public health application: 1. We submittedabstracts to the annual International Food Technology meeting in 2016, as well asthe American Society of Nutrition meetings in 2018 and 2019, presenting our results in both poster and oral formats. Thesemeetings areattended by many basic and clinical scientists interested in nutrition and cancer prevention. 2. I have presented our findings at multipleresearch seminars both domestically (the Gastroenterology Division at Massachusetts General Hospital/Harvard Medical School) and internationally (University of Lorraine, Nancy, FRANCE). The attendees at each of these meetings were both investigators and clinicians whose interests include the nutritional prevention ofcancer. 3. We have submitted a provisional patent application to the U.S. patent office based on our findings, thus disseminating our scientific advancesin a publically-availableformat that will possibly facilitate its translation into a commercially-viable product. Changes/Problems:1. The strain of mice we had used for prior experiments in which we explored strategies for suppressing obesity-promoted colon carcinogenesis was the A/J strain. We found this animal to be sub-optimal since it is relatively resistant to the induction of diet-induced obesity. To circumvent this problem we switched to a strain that is both susceptible to diet-induced obesity and sensitive to AOM-induced carcinogenesis, the FVB strain. This proved to be a successfulmeans of addressing this problem. 2. We have yet to developa methodology we are satisfied with thatis stable and which predictablynanopackages these agents for colon-specific delivery. We plan to continue seeking a suitable means eventhough the project period has ended. What opportunities for training and professional development has the project provided?Constructing the details of experimental design, conducting theanimal experiments, analyzing the samples, and analyzing the data wereperformed by Dr. Mason's post-doctoral fellow under Dr. Mason's close supervision, providing an excellent platform for training this individual. She has now graduated from her post-doctoral training and acquired a position as an Assistant Professor at an american university. An ongoing analysis of tissuesamples and data in collaboration with Dr. Mason isproviding a robust means for her to continue her research productivityas she sets up her own lab and transitions to thisfirst faculty appointment. How have the results been disseminated to communities of interest?Over the course of the entire project periodwe have disseminated our observationstothe scientific community on multiple occasions (#1 and 2, below). Also, in order to enablethe general public to benefit from our results, we disseminated our advances in the format of a provisional patent application, thereby initiatingthe process wherebythis research may be translated to a product for the good of public health. 1. We have submittedabstracts to the annual International Food Technology meeting in 2016, and the American Society of Nutrition meeting in 2018 and 2019, presenting our results in both poster and oral formats. Thesemeetings areattended by many basic and clinical scientists interested in nutrition and cancer prevention. 2. I have presented our findings at multipleresearch seminars both domestically (the Gastroenterology Division at Massachusetts General Hospital/Harvard Medical School) and internationally (University of Lorraine, Nancy, FRANCE). The attendees at each of these meetings were both investigators and clinicians whose interests include the nutritional prevention ofcancer. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Goals #1 and #2. In a mouse model of obesity-promoted colon cancer we demonstrated that co-administration of 0.2% curcumin and vitamin B6 at 4-times the basal requirement (CUR/B6) resulted in a 64 and 78% reduction in tumor multiplicity and tumor burden compared to the corresponding tumor metrics observed in the control obese group (p<0.04). In contrast, neither agent by itself was sufficient to produce a significant reduction in these tumor metrics. The reduction in tumor burden in the CUR/SAL group was 3-fold greater compared to curcumin alone and 2-fold greater than B6 supplementation alone. Mechanistically, we have shown that the combination regimen is also superior to either agent alone in suppressing pro-carcinogenic Wnt and NFkB signaling. We have also examined elements of the sphingosine-1-P04 and kyneurinine pathways as a means of delineating the means by which B6 supplementation suppresses tumorigenesis. Goal #3. We have encountered a number of technical issues in successfully packaging these agents for colon-specific delivery and are continuing to work towards a methodology that is reproducibly effective.
Publications
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2016
Citation:
Mason JB. Preventing Obesity-Promoted Cancers by Utilizing Bioactive Components and Nanoparticle Packaging Technologies. (International Food Technology meeting, 2016)
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2018
Citation:
Wu X, Koh G-Y, Crott J, Mason JB. The combination of curcumin and vitamin B6 suppresses high fat diet-induced colorectal tumorigenesis in azoxymethane-treated mice (American Society for Nutrition, annual meeting)
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2019
Citation:
Wu X, Koh GY, Crott J, Mason JB. Vitamin B6 and Curcumin Supplementation Is Superior to Either Agent Alone in Suppressing Pro-carcinogenic Signaling and Colorectal Tumorigenesis in Obese Mice (American Society for Nutrition, annual meeting)
|
Progress 12/01/17 to 11/30/18
Outputs
Target Audience:In order to disseminate scientific information arising from this work we have reached two target audiences during this reporting period: 1. We submitted an abstractduring the reporting period that willbe presented either as a poster or as a talk at the 2019 American Society for Nutrition meeting. This meeting is attended by many basic and clinical scientists interested in nutrition and cancer prevention. 2. I gave a research seminar on 'Mechanisms of obesity-promoted colorectal cancer and its prevention' to the Gastroenterology Division at Massachusetts General Hospital/Harvard Medical School during this reporting period. The attendees were both investigators and clinicians whose interests include the nutritional prevention of colorectal cancer. Changes/Problems:We have notyetsucceeded in developinga methodology to reproducibly nanopackage these agents for colon-specific delivery in a vehicle that is stable enough to add to diets. What opportunities for training and professional development has the project provided?Constructing the details of experimental design, conducting the trial, analyzing thesamples, and analyzing thedata have each been performed by Dr. Mason's post-doctoral fellow under Dr. Mason's close supervision, providing an excellent platform for training this individual. How have the results been disseminated to communities of interest?1. We submitted an abstractduring the reporting period that willbe presented either as a poster or as a talk at the 2019 American Society for Nutrition meeting. This meeting is attended by many basic and clinical scientists interested in nutrition and cancer prevention. 2.Dr. Masongave a research seminar on 'Mechanisms of obesity-promoted colorectal cancer and its prevention' to the Gastroenterology Division at Massachusetts General Hospital/Harvard Medical School during this reporting period. The attendees were both investigators and clinicians whose interests include the nutritional prevention of colorectal cancer. What do you plan to do during the next reporting period to accomplish the goals?During the remainder of the project period we are: 1.Working with the blood and tissue samplesfrom our mouse study to delineate the molecular pathways by which the CUR/SAL regimen diminished tumorigenesis. Wedetermined that the combination of CUR/B6 significantly down-regulated several critical pro-carcinogenic signaling pathways in the colon, including PI3K, Wnt and NF-κB (p<0.05). Importantly, the suppression produced by the combination was much more robust than did CUR or B6 alone, although B6 alone did produce a significant inhibition of the Wnt pathway. 2. Continuing work aimed at nano-packaging the agents for colon-specific delivery.
Impacts
What was accomplished under these goals?
Goals #1 and #2. In a mouse model of obesity-promoted colon cancer we demonstrated that co-administration of 0.2% curcumin and vitamin B6 at 4-times the basal requirement(CUR/B6) resulted in a 64 and 78% reduction in tumor multiplicity and tumor burden compared to the corresponding tumor metrics observed in thecontrol obesegroup (p<0.04). In contrast, neither agent by itself was sufficient to produce a significant reduction in these tumor metrics. The reduction in tumor burden in the CUR/SAL group was 3-fold greater compared to curcumin alone and 2-fold greater than B6 supplementation alone. Goal #3. We have encountered a number of technical issues in successfully packaging these agents for colon-specific delivery and are continuing to work towards amethodology that is reproducibly effective.
Publications
- Type:
Conference Papers and Presentations
Status:
Submitted
Year Published:
2019
Citation:
Xian Wu, Gar Yee Koh, Jimmy Crott, Joel Mason. The vitamin B6 and curcumin co-treatment is superior to either agent alone in suppressing pro-carcinogenic signaling and colorectal tumorigenesis in obese mice. (submitted to 2019 ASN meeting, to be published in Current Developments in Nutrition)
|
Progress 12/01/16 to 11/30/17
Outputs
Target Audience:The target audience reached by our efforts during this reporting periodwas the community of researchers whose focus is on using nutrition or medicinal approaches to the chemoprevention of colorectal cancer. Changes/Problems:This project necessitated that we utilize a mouse strain that is both susceptible to the induction of obesity with a high-fat diet and is sensitive to the carcinogen, DMH: a requirement that is not present in many conventional strains. Thus, wewere compelledto explore new strains that we had not previously utilized. Several literature reports indicated that four doses of DMH (at 10 mgs/kg body weight) would be sufficient to produce an average of several tumors per mouse in our selected strain. However, we found that this was inadequate and have now switched to amore aggressive dosing regimen that is recommended by other papers. What opportunities for training and professional development has the project provided?Funding for this project has supported the majority ofDr. Xian Wu'sefforts in Dr. Mason's laboratory. She is a postdoctoral associate in her second year of training. Based largely on the work funded by this project she recently submitted a fellowship grant to the American Federation for Aging Research, andrecently interviewed for a junior faculty position at Bowling Green University. Her scientific acumen, knowledge base, grant-writing skills andlaboratory capabilities, and thus her ability to succeed as an independent investigatorhave been greatly expanded by her support. How have the results been disseminated to communities of interest?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?Goals #1 & #2: The animalsdue to be sacrificed in April and the ensuing analysis of their tumors and signaling pathwayswill provide us with definitive answers to these two goals. Goal #3: We are continuing to refine our ability to nanopackage the components of the combination regimen. Our experiments to date indicate that bioavailability of the curcumin to the colon is excellentwithout nanopackaging, so we are focusing instead on nanopackaging the vitamin B6 since it tends to be absorbed much higher up in the intestine and is not particularly bioavailable to the colonic mucosa.
Impacts
What was accomplished under these goals?
Goal #1:The initial mouse study conducted in the prior reporting year proved to be inadequate to meet our primary goal of examining modulation of tumorigenesisbecause the animals proved to be more resistant to the carcinogen, DMH, than was reported in the literature. We have since initiated a new study with 116 animals usinga more intensive dosing regimen of DMH. This most recent experiment is proceeding well: the high-fat animals are approximately15% heavier than the low-fat animals and only 2 animals have died, with 10 weeks to go before final sacrifice of all the animals. Goal #2: When the mice described underGoal #1 are sacrificed in 10 weeks we shall be able to delineate the relative efficacies of the two agents alone, versus the two in combination.
Publications
|
Progress 12/01/15 to 11/30/16
Outputs
Target Audience:To date, the target audiences that have been reached by my research efforts on this project include: 1) scientists who are interested in using novel dietary and nutritional strategies to prevent cancer, and 2)individualsother than scientists who belong to the food technology industry. Changes/Problems:Although several papers in the literature indicate that a high-fat diet can readily induce obesity in the strain of mice originally proposed for our experiments (the 'A/J' strain), we have found them relatively resistant to the acquisition of an obese phenotype. For our next experiment we have therefore chosen to change to another strain of mouse that is widely recognized as one that develops obesity and which issensitive to the tumorigenic effects of the carcinogen we use, AOM. The strain we have chosen is the C57 L/J. What opportunities for training and professional development has the project provided?Funding for this project has enabled the PD to hire a postdoctoral fellow who developed an interestin the nutritional chemoprevention of cancer during her work as a Ph.D. student. Hertechnical and intellectual skills have been markedly expanded by taking on a major role in conducting this project. How have the results been disseminated to communities of interest?To date, I have reported on the nature of our ongoing project to two groups of scientists outside of my university. I presented ata scientific symposium entitled 'Opportunities for Research and its Funding Across Food Science and Nutrition: Bridging the Gap!' at the annual International Food Technology (IFT16)meetingin Chicago and at the research seminar in the Department of Pathobiology at University of Connecticut. What do you plan to do during the next reporting period to accomplish the goals?We plan to make onechange of substance in the research plan that was originally approved: Although several papers in the literature indicate that a high-fat diet can readily induce obesity in the strain of mice originally proposed for our experiments (the 'A/J' strain), we have found them relatively resistant to the acquisition of an obese phenotype. For our next experiment we have therefore chosen to change to another strain of mouse that is widely recognized as one that develops obesity and which issensitive to the tumorigenic effects of the carcinogen we use, AOM. This strainis the C57 L/J.
Impacts
What was accomplished under these goals?
Adults in the U.S.who are overweightor obese, whichcomprises two-thirds oftheadult population, are at much higher risk of developing colorectal cancer. The long-termgoal of this project is toestablish the efficacyand optimize the performanceof a novel dietary regimen enriched in two food componentsthat suppresses the inflammation that resides in the colon of obese individuals, and thereby mitigate the elevated risk of the cancers in these individuals.This dietary regimen consists of a combination of vitamin B6 and the dietary polyphenol, curcumin: when administered in supplemental quantities each of these two agents is very effective in suppressing inflammation in the colon. In order to optimize performance we shall examine the synergy when the agents are used in combination and alsodetermine whether packaging these agents in a novel nanoparticle vehicle that targets its delivery to the colon will enhance the cancer preventive properties of the regimen. The change inknowledge generated by this project will potentiallyhave a very largeimpact since it will provide the scientific basis forclinical trials, and subsequent widespread use, of a dietary regimen that willmarkedly reduce the societal burden of the third most common cause of cancer death in the U.S. Goal #1. Determine the extent to which the endpoint of ultimate relevance--the development of obesity-associated colorectal neoplasms--is inhibited by the combination of vitamin B6 and curcumin, and begin to define an optimally effective tumor-suppressive dose of this combination regimen. We have successfully set up the proposed mouse study to examine the tumor suppressive effects of the combination regimen and are scheduled to sacrifice the animals later this spring. Of the 116 mice in this experiment, only 5 have died prematurely, which should leave us more than enough animals to answer the research questions posed by this experiment. Goal #2. By using a factorial design, delineate the relative chemopreventive potencies of vitamin B6 and curcumin as individual agents, and compare the extent to which combining the two offers multiplicative protection against obesity-promoted tumorigenesis. When the mice described under Goal #1 are sacrificed and tumor load is determined in each of the groups, we shall be able to delineate the relative efficacies of each of the two agents alone, and in combination. Goal #3. Examine whether packaging the B6 and curcumin in a novel nanoparticle system that targets delivery to the colon potentiates the tumor-suppressive properties of the combination regimen, therby improving the efficacy of cancer prevention and diminishing the required amounts of curcumin and B6. We have conducted a series of in vitro experiments, examining nanoparticles of varying composition and have identified a nanoparticle that does not release its contents in the electrochemical environment of the small intestine but promptlyreleases 75-80% of its contents when exposed tothe electrochemical environment of the colon. These particles will be utilized in the next animal experiment.
Publications
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2016
Citation:
Title of presentation at IFT16: Preventing Obesity-Promoted Cancers by Utilizing Bioactive Components and Nanoparticle Packaging Technologies
|
|