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Can Natural Products Treat Triple Negative Breast Cancer (TNBC)?
Can Natural Products From Papua New Guinea Treat Triple Negative Breast Cancer?Matt BirrenkottPharmD Candidate, 2018October 19th, 2015
ObjectivesIntroductionBackgroundTNBCNatural Products (NP)Dynamic RewiringThe ExperimentResultsConclusion and what next?
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IntroductionBarrows LabNatural Products (NP)Papua New GuineaHIVTBTriple Negative Breast Cancer (TNBC)
Triple Negative Breast Cancer (TNBC)
Hormone ReceptorsNegative for estrogen, progesterone, HER-2Soltamox (tamoxifen), Herceptin (trastuzumab)TreatmentCytotoxic chemotherapyRisk of infection, cardiotoxicity, neurotoxicity, nausea and vomiting (Abramson, 2015)StatisticsApproximately 15% of breast cancersRecurrence 34%Aggressive and higher mortality Higher prevalence in younger and African American women (Schmadeka, 2014)
Recurrence compare to about 20% in non TNBC breast cancer4
Natural Products and MedicineNatural Products (NP)50% of clinical drugsAspirin, morphine, penicillins, cephalosporins, vincristine, doxorubicin, etc. (Gurib-Fakim, 2006)
http://www.pngtours.com/jungle.html
Define natural products. Compounds or substance created by a living organism in nature5
Nobel PrizeOctober 5, 2015Youyou TuPharmacistMedical ScientistPharmaceutical Chemist
Potent Anti-Malarial
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2015/press.html
chinese Traditional Medicines6
Papua New Guinea (PNG)Biological Diversity1% of the Earths land has 6% of all biological diversity3rd largest closed canopy rain forestMuch has yet to be scientifically explored
Barrows, 2010
(PNG Conservation Needs Assessment Map, 1992)
Shares an island of indonesia. 600 islands7
PNG and Traditional MedicinesCultural DiversityOver 800 languagesLong tradition of medicinal plant useTraditional MedicinesPharmacy Students collect Document cultureExtraction Libraries created
http://www.pngtours.com/huliculture.html
Medicine man or herbal healer or traditional practitioner8
Dynamic Rewiring(Lee and colleagues, 2012)
Sequential drug administration with erlotinib (EGFR inhibitor)
Revealing apoptotic pathways
Efficacy of Doxorubicin
Figure 1, C. Image from Lee et al., 2012.
Caspase 8 activation. X-Axis is the different conditions of experimentsErlotinib used for lung and pancreatic cancer9
DMSODOX/ErlErl -> DOXDOXErl
Apoptotic Markers: Cleaved PARP and Cleaved Caspase 3
ExperimentHypothesis: Natural products from Papua New Guinea have potential cell rewiring effects to increase the efficacy of DNA damaging drugs (e.g. doxorubicin) against TNBC
DesignMDA-MB-231 cell line from Huntsman Cancer InstituteTNBC human cellsNatural Product Libraries (Traditional Medicines)16 different plant-based librariesExperimental groupNatural products administered sequentially before doxorubicin (NP DOX)ControlsDMSO, DOX, NP, DOX/NP, and DOX NP
ExperimentDay 1: Plating Cells
4 days to screen 1 library13
ExperimentDay 2: First Treatment 24 hour gapDay 3: Second Treatment
Conditions:NPDOXNP/DOXNP DOXDOX NPhttps://healthy.kaiserpermanente.org/static/drugency/images/TEV50460.JPG
ExperimentDay 4: Analyze
https://en.wikipedia.org/wiki/MTT_assay
Data
Tested over 800 fractions
Soil used topically for stomach aches
10 um (lee) 0.05 um (me)17
Natural Product Extraction
Separation
Separation With HPLCHigh Performance Liquid ChromatographyReverse Phase
(Larson et al., 2014)
ConclusionNP from Papua New Guinea do have potential cell rewiring effects making doxorubicin more effective that require further investigation
What Now?Test HPLC fractionsStructure elucidation of active compounds (mass spec, NMR , etc)Selectivity to TNBC cells?Determine mechanism of action (FLOW, Western blots)
FundingWheeler FoundationNon-profit philanthropic group Salt Lake City, UT
ICBG (International Cooperative Biodiversity Groups)Biodiversity and its use in healthDrug discovery from natural Products
AcknowledgementsBarrows LabDr. Chris PondDr. Louis BarrowsErica LarsonMackenzie YedlinAlessandra Miranda
University of Utah College of PharmacyDr. FranklinDr. Herron
ReferencesAbramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA. Subtyping of triple-negative breast cancer: implications for therapy. Cancer. 2015;121(1):8-16.
Schmadeka R, Harmon BE, Singh M. Triple-negative breast carcinoma: current and emerging concepts. American journal of clinical pathology. 2014;141(4):462-477.
Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Molecular aspects of medicine. 2006;27(1):1-93.
Barrows LR, Matainaho TK, Ireland CM, et al. Making the most of Papua New Guinea's biodiversity: Establishment of an integrated set of programs that link botanical survey with pharmacological assessment in "The Land of the Unexpected". Pharmaceutical biology. 2009;47(8):795-808.
Lee MJ, Ye AS, Gardino AK, et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell. 2012;149(4):780-794.