Nutritional Perspectives on Cancer


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In as few words as possible, this presentation describes the state of the science on the use of nutrients in the battle against cancer. This presentation is heavily referenced from the peer-reviewed medical literature which state that nutrients are both bonafide chemotherapeutic agents on their own and adjuvant compounds

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Nutritional Perspectives on Cancer

  1. 1. Nutritional Perspectives on Cancer A Primer for ChiropractorsAndrew S. Bonci, BA, DCMission,
  2. 2. A Special Thank You And All● Missouri State Chiropractic Association ● Dr. Robert Riley ● Dr. Ron Manfredi ● Dr. Russell Matthias of You! ● Dr. Doran Nicholson
  3. 3. Get the Notes Obtenga las Notas Akiru la Notojn
  4. 4. Disclosures I work for NO special interest orlobbying groups nor do I receive stipends, consulting fees, gratuities or honoraria from any pharmaceutical or nutritional companies. I am NOT a fan of Big Pharma or sell-out government officials and this may show. 4
  5. 5. Nel mezzo del cammin di nostra vita mi ritrovai per una selva oscura ché la diritta via era smarrita. ~ Dante Alighieri ~
  6. 6. Midway through the journey of my life I found myself lost in a dark forest, Having wandered off the main path. It is hard for me to express in wordsHow savage, rough, and stern this forest was to me. The very thought of it renews my fear. It was so bitter that death could not be worse; But in order to show you the good that I eventuallyfound, I must first tell you of the other things I saw. I cannot remember how I entered the forest, My thoughts were full of other things When I wandered off the path. ~ Dante Alighieri ~
  7. 7. Objectives Contextualize Nutrition in Genetic Terms Look at Nutrition from the Perspective of Pancreatic Cancer Examine Nutrient Control of Cell Cycle and Signal Processing Explore Nutrients as Chemoprotective and Chemotherapeutic Agents Hazard an Approach to a Healing Poetry “Sanapoesis” 7
  8. 8. Objectivos Contextualizar la Nutrición en Términos Genéticos Mirar a la Nutrición desde la Perspectiva de Cáncer Pancreático Examinar el Control Nutricional del Ciclo Celular y Procesamiento de Señales Explorar Nutrientes como Agentes Quimioterapéuticos y Quimioprotectores Aventurar una Aproximación a una Poesía Sanadora o “Sanapoesis" 8
  9. 9. Celoj Kuntekstigi Nutradon en Genetikaj Terminoj Rigardi Nutradon de la Perspektivo de Kancero Pankreata Ekzameni Nutran Kontrolon de Ĉela Ciklo kaj Signala Procesorado Esplori Nutraĵojn kiel Kemiprotektaj kaj Kemiterapiaj Agentoj Riski Alproksimiĝo al Resaniga Poezio aŭ "Sanapoesis" 9
  10. 10. Objections Cancer is a Medical Diagnosis. Chiropractors dont Diagnose or Treat Medical Conditions.How is “this” Chiropractic? 10
  11. 11. No man is an Iland, intire of it selfe; every man is a peece of the Continent, a part of the maine; if a Clod bee washed away by the Sea, Europe is the lesse, as well as if a Promontorie were, as well as if a Mannor of thy friends or of thine owne were; any mans death diminishes me, because I aminvolved in Mankinde; And therefore never send to know for whom the bell tolls; It tolls for thee. 11
  12. 12. Cancer, like any form of human suffering, is for me Chiropractic because … “I am involved in Mankinde” 12
  13. 13. The Soul always knows what to do to heal itself. The challenge is to Silence the Mind. Carolyn Myss Photo by Dr. Marcos Lerma
  14. 14. ProseLatin word prōsa (“straightforward”) from the term prōsa ōrātio Prosaic … commonplace or dull; matter-of-fact or unimaginative: a prosaic mind.
  15. 15. Poetry from the Greek poiesis — ποίησις —with a broad meaning of a "making" or “creating”, seen also in such terms as "hemopoiesis" ...… as opposed to the prosaic ostensible meaning.
  16. 16. Dedicated to the Poetry and ... … Michele.… Poise which is ...
  17. 17. Intellect takes you to the door,but it doesn’t take you into the house. ~ Shams Tabrizi ~
  18. 18. A Systematic Failure There is a systematic failure in our present culture to see meaning on multiple, interweaving levels. This has brought us to a literal, uninspired and disastrous interpretation of life, health and disease.King Philip the “Fair” of France and Pope Clement V accused the Templars of atheism, sodomy, blasphemy, and worse. Templars were tortured into forced confessions before www.drbonci.combeing executed in large numbers. Scholars have debated whether any charges were true, but it is believed that they were innocent of the accusations and the process againstthem was solely for gaining access to their wealth and to ensure they could not become a political threat.
  19. 19. What v. How to Think About NutritionI want to loosen my sense of “what” nutrition is asdefined in a strictly traditional sense.● A tradition is a ritual, belief or object passed down within a society, still maintained in the present, with origins in the past.Thomas A. Green (1997). Folklore: an encyclopedia of beliefs, customs, tales, music, and art. ABC-CLIO. pp. 800–. ISBN 978-0-87436-986- 1.Latin stem of “trāditiō” means both “tradition” and “treason”I would like to open myself up to new ways toconceptualize how cells interpret the meaning ofmacronutrients and micronutrients.
  20. 20. Industrial Revolution NutritionFood as fuel that powers the machinery of the body Vitamins and minerals as co-enzymes and metabolic co-factors in energy production Krebs Cycle 20
  21. 21. Nutrients are Simply Raw Materials In the old, and still prevailing world view,nutrients are measured quantities of raw materials used as building blocks that are supplied to repair hardware and renew energy. 21
  22. 22. Information Age NutritionNutrients are environmentalsignals.Seasonality of foods tellsthe inside whats going onoutside.Food availability may markcircannual rhythms on acellular level. 22
  23. 23. Dutch Famine of 1944The Dutch famine of 1944 was a famine that took place in the German-occupied part of the Netherlands. A German blockade cut off food and fuel shipments from farm areas to punish the reluctance of the Dutch to aid the Nazi war effort. Some 4.5 million people were affected and survived because of soup kitchens. Henri A. van der Zee, The Hunger Winter: Occupied Holland 1944-1945 (1998) pp. 304-305 23
  24. 24. Dutch Famine SurpriseThe children of pregnantwomen exposed to thefamine were moresusceptible to diabetes,obesity, cardiovasculardisease,microalbuminuria andother health problems.Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16757-8. 24
  25. 25. Dutch Famine Surprise[T]he children of thewomen who werepregnant during thefamine were smaller, asexpected.However, surprisingly,when these childrengrew up and hadchildren those childrenwere also smaller thanaverage. Epigenetics. 2009 Nov 16;4(8):526-31. 25
  26. 26. Can You See the Three Generations Present in This Photo? 26
  27. 27. Perhaps one can beat cancer and heart disease with food as well. “Unlike curing cancer or heart disease,we already know how to beat hunger: food.” Mario Batali
  28. 28. Mors et vita in manu linguae qui diligunt eam comedent fructus eius. (Proverbs 18:21 Vulgate)
  29. 29. How Might We Understand Food?Food is more than fuel topower the metabolicengine.Nutrients are more thanfodder to stoke the cellularfurnace.Food is information as wellas fuel.Nutrients are cellular orenvironmental signals. 29
  30. 30. What was Old is New Again The recognition that nutrients have the ability to interact and modulate molecular mechanisms Let Food beunderlying an you Medicine,and Medicine be your Food. organism’s physiological functions has prompted a revolution in the field of nutrition.FASEB J. 2005 Oct;19(12):1602-16.
  31. 31. IntroducingNutrigenetics
  32. 32. NutrigeneticsNutrigenetics aims to understand how the geneticmakeup of an individual coordinates theirresponse to diet, and thus considers underlyinggenetic polymorphisms. Curr Opin Lipidol. 2004 Apr;15(2):101-8.● In other words, nutrigenetics embodies the science of identifying and characterizing gene variants associated with differential responses to nutrients, and relating this variation to disease states. Annu Rev Genomics Hum Genet. 2004;5:71-118.
  33. 33. PolymorphismPolymorphism in biology occurs when two ormore clearly different phenotypes exist in thesame population of a species. polymorphism is a common change in thegenetic code in DNA. can have a harmful effect, a goodeffect, or no effect. Some polymorphisms havebeen shown to increase the risk of certain types ofcancer.
  34. 34. Polymorphisms are CommonPolymorphism is common in nature. It relates tobiodiversity, genetic variation and adaptation.It functions to retain variety of form in a populationliving in a varied environment.● The most common example is sexual dimorphism, which occurs in many organisms. Other examples are human hemoglobin and blood types.
  35. 35. Each of us is a Polymorph ... Lets imagine that the pants factory makes ONLY size medium trousers since this isNow, lets imagine that aits been provendosage Now, lets imaginesize, arecommended by the “average” that recommended daily research and mandated by law ... of chemotherapy/medicine were established requirement of nutrients were established because it is an “average” requirement, its been proven and mandated by law ...
  36. 36. Genetic PolymorphismsPolymorphisms are not mutations, per se.A polymorphism is an allelic variation.These allelic variations result in a variety or broadspectrum of protein/enzyme forms.The broad spectrum of protein or enzyme formsmanifests itself in broad spectrum functionality.These polymorphs will have a need for full-spectrum nutritional support in order to encounterthe “necessary nutrient blends.”
  37. 37. Importance of Whole FoodsFull-spectrum, whole food supplementationprovides the broad co-factor/coenzymecomplement to ensure optimal functionality to theindividualized polymorphic expressions.Polymorphisms cannot accommodate to a diet ofprocessed foods for the lack of the full-spectrumenvironmental/nutritional signals.
  38. 38. Current Extinction Episode The modern diet is, in effect, an evolutionary pressure that isforcing an extinction episode to which we are real-time witnesses.The incompatibility between common polymorphic expressions and the modern mono-cultural, highly processed diet appears to be a force in the causation of “disease” and, consequently, our extinction … or evolution … ?
  39. 39. According to Andreas Moritz, cancer is a desperate and final attempt by the body to stay alive for as long as circumstances permit. He presents a provocative thesis and does a crappy job of defending
  40. 40. If Cancer were a Survival Mechanism ...It would probably be because:● The modern, highly processed diet is devoid of the environmental signal required to supply the full spectrum, polymorphic needs of the cells.● Having unfulfilled needs, these cells would break their bonds with the their once vibrant cellular communities.● They would form a cellular “subculture” and live as “tissue” outcasts until they amassed sufficient numbers to command greater resources in order to ensure their survival.● When environmental-nutrient signal and metabolic resources become further strained, these renegade cells would aggressively try to satisfy their unmet needs by leaving their malignant communities.
  41. 41. Societal interactions in ovarian cancer metastasis: a quorum-sensing hypothesisQuorum sensing is a bacterial cell-cellcommunication process used to track increasingcell-population density and, in response tochanges in cell number, coordinate geneexpression and behavior on a community-wide scale. scale ● Cells migrate toward/on target surfaces (organ-specific homing), show cell-cell and cell-matrix interactions (tumor cell- stromal cell crosstalk), remain subclinical until they can mount an effective attack (dormancy), form complex structures with channels for nutrient flow (vascularized lesions), and contain resistant cells which can cause disease recurrence (persistors).Clin Exp Metastasis. 2009;26(1):67-76.
  42. 42. It may in fact be, that the very essence of whatindividuals have to offer the world is through a closeunderstanding of their weaknesses and blind spots. ~David Whyte~ 42
  43. 43. My Ultimate FocusDr. Michele A. Bonci● Pancreatic Cancer (2012)● Breast Cancer (1998)● Lupus (1996) 43
  44. 44. This moment is all there Is. ~ Rumi 44
  45. 45. Prior to June 15, 2012 Vague and generalized lower back and flank pain. Difficulty getting comfortable. Bloating and general abdominal discomfort after eating. 45
  46. 46. June 15, 2012 Abdominal ultrasound demonstrates a large solid tumor mass in the head of the pancreas. CT scan confirms the findings of the abdominal ultrasound. We are fully aware of our odds and begin planning for the worst. 46
  47. 47. "My scheduled busyness was awonderful measure of my self-importance." ~David Whyte~ 47
  48. 48. June 21, 2012 Jaundice becomes obvious by 3:00PM. Serum tests become positive for the first time for elevated bilirubin and alkaline phosphatase. Exponential growth and doubling time press on our minds. 48
  49. 49. S. Faisal Jafri, MD Places a common bile duct stent to remove obstruction. Endoscopic ultrasound examination confirms the mass, identifies local lymph node swelling and unusual liver appearance. She is diagnosed with Stage III Pancreatic Cancer. Referral is made to Jaswinder Singh, MD 49
  50. 50. Jaswinder Singh, MD Very receptive to our input into cancer care and management. Expressed a desire to use a standard chemotherapeutic agent approved for use in pancreatic cancer. Entertained a detailed discussion on nutritional co-management for cancers in general and pancreatic cancer in particular. 50
  51. 51. GEMZAR (Gemcitabine) ®
  52. 52. HIGHLIGHTS OF PRESCRIBING INFORMATION--------------------- INDICATIONS AND USAGE --------------------Gemzar® is a nucleoside metabolic inhibitor indicated for: ● Ovarian cancer in combination with carboplatin ● Breast cancer in combination with paclitaxel ● Non-small cell lung cancer in combination with cisplatin ● Pancreatic cancer as a single-agent
  53. 53. HIGHLIGHTS OF PRESCRIBING INFORMATION----------------- DOSAGE AND ADMINISTRATION ---------------Gemzar is for intravenous use only. ● Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks ● Dose Reductions or discontinuation may be needed based on toxicities.
  54. 54. HIGHLIGHTS OF PRESCRIBING INFORMATION------------------------- CONTRAINDICATIONS ------------------------Patients with a known hypersensitivity to gemcitabine----------------- WARNINGS AND PRECAUTIONS ---------------- ● Hematology: Monitor for myelosuppression, which can be dose-limiting. ● Pulmonary toxicity: Discontinue Gemzar immediately for severe pulmonary toxicity.
  55. 55. DescriptionGemzar (gemcitabinefor injection, USP) is anucleoside metabolicinhibitor that exhibitsantitumor activity.Gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidinemonohydrochloride.
  56. 56. Mechanism of ActionGemcitabine exhibitscell phase specificity,primarily killing cellsundergoing DNAsynthesis (S-phase)and also blocking theprogression of cellsthrough the G1/S-phaseboundary.
  57. 57. What Can We Do Supportively?
  58. 58. Indole-3-Carbinol(s)Enhance the the effectiveness of GEMZAR atlower dosages Enhanced efficacy of gemcitabine by indole-3-carbinol in pancreatic cell lines: the role of human equilibrativenucleoside transporter 1. Anticancer Res. 2011 Oct;31(10):3171-80.Decrease the toxicity of GEMZARefficacy in cancer cells: effect of indole-3-carbinol. Anticancer Res. 2010 Dec;30(12):4907-13. Gender differences in gemcitabine (Gemzar)Decrease the metastatic potential through itsaction of elastase(s), et. al. The dietary phytochemical indole-3-carbinol is a natural elastaseenzymatic inhibitor that disrupts cyclin E protein processing. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19750-5. Direct inhibition of elastase activityby indole-3-carbinol triggers a CD40-TRAF regulatory cascade that disrupts NF-kappaB transcriptional activity in human breast cancer cells. Cancer Res. 2010Jun 15;70(12):4961-71.Convey endogenous antioxidant effects to thepancreas during chemo and radiation therapies.Induction of rat pancreatic glutathione S-transferase and quinone reductase activities by a mixture of glucosinolate breakdown derivatives found in Brusselssprouts. Food Chem Toxicol. 1998 May;36(5):365-73.
  59. 59. Curcuminoid(s)Increase induction of apoptosis and decreaseVEGF in pancreatic cells. Gemcitabine sensitivity can be induced in pancreatic cancer cells throughmodulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res. 2010 May 1;70(9):3606-17.Sensitizes pancreatic cancer cells to gemcitabine.Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, andinhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007 Apr 15;67(8):3853-61.Delay or eliminate development of resistance togemcitabine. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer throughsuppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007 Apr 15;67(8):3853-61.
  60. 60. MelatoninReduction in pancreatictumor viability andproliferation. Melatonin reduces pancreatic tumorcell viability by altering mitochondrial physiology. J Pineal Res. 2011Apr;50(3):250-60.Promote apoptosis ofabnormal tissue whilepreserving normaltissue. Melatonin induces pro-apoptotic signaling pathway inhuman pancreatic carcinoma cells (PANC-1). J Pineal Res. 2010Oct;49(3):248-55.
  61. 61. Circadian RhythmTiming of Chemotherapy to reduce the risk ofmyelosuppression.The relationship between treatment time of gemcitabine and development of hematologic toxicity in cancer patients. Biol Pharm Bull. 2011;34(11):1765-8.
  62. 62. Broad Spectrum ApproachIn vitro and in vivo studies have demonstratedthat some natural products such as isoflavones,indole-3-carbinol (I3C), 3,3′-diindolylmethane(DIM), curcumin, (−)-epigallocatechin-3-gallate(EGCG), resveratrol, lycopene, etc, haveinhibitory effects on human and animal cancersthrough targeting multiple cellular signalingpathways and thus these “natural agents” couldbe classified as multi-targeted agents.Cell Signal. 2009 Nov;21(11):1541-7.
  63. 63. “Where you stumble and fall,there you will find gold.” ~Joseph Campbell~ 63
  64. 64. 64
  65. 65. First Gemzar Infusion 65
  66. 66. Jay Robinow, MD Radiation directed at the pancreatic mass and surrounding vessels. Very open to our participation as chiropractors. Was very excited to speak with us as co- professionals. 66
  67. 67. Waiting to be Irradiated 67
  68. 68. First Hospitalization 68
  69. 69. A Deepening of AwarenessBy regulating multiple important cellular signalingpathways including NF-κB, Akt, MAPK, Wnt,Notch, p53, AR, ER, etc, [...] natural products areknown to activate cell death signals and induceapoptosis in pre-cancerous or cancer cellswithout affecting normal cells.Cell Signal. 2009 Nov;21(11):1541-7.
  70. 70. Second Hospitalization 70
  71. 71. Natural Chemotherapeutic AgentsTherefore, nontoxic “natural agents” harvestedfrom the bounties of nature could be useful eitheralone or in combination with conventionaltherapeutics for the prevention of tumorprogression and/or treatment of humanmalignancies.Cell Signal. 2009 Nov;21(11):1541-7.
  72. 72. Stop acting so small.You are the universein ecstatic motion.~ Rumi ~ 72
  73. 73. Joe Cates, MD Consummate surgeon. Was very excited to speak in “big boy” anatomical terms with us. Treated us as intelligent co-professionals. Did an amazing job as a compassionate surgeon. 73
  74. 74. September 20, 2012 74
  75. 75. Whipple Procedure 75
  76. 76. The Specimen 76
  77. 77. The Post-Operative Patient 77
  78. 78. The Complications● Thrombosed and damaged superior mesenteric vein (SMV). Atypical/cancerous cell mass remains in the What to do?● damaged SMV.● Very poorly tolerated chemotherapy. 78
  79. 79. The Post-Operative GoalMaximize Life-ExpectancyEliminate CancerPain ControlRestore Health 79
  80. 80. The Post-Operative PlanAdditional Radiation to SMVAggressive Nutritional Intervention Adjuvant TPN Adjuvant Oral Nutrition 80
  81. 81. Adjuvant TPN● Osmolite 1.2 Cal● Adjuvant Nutrition ● Bluberry Fruit Extract ● Milk Thistle Extract ● Green Tea Extract ● Dandelion Extract ● Colloidal Minerals 81
  82. 82. Adjuvant Oral NutritionMelatonin (300mg/1-2 hours)GABA (125mg/1-2 hours)Mixed Carotenes (25,000IU)Vitamin D3 (5,000IU/6 hours)Silymarin (375mg/2 hours) 82
  83. 83. Are you sure it is safe to take all those vitamins? 83
  84. 84. Nutrigenomics Nutrigenomics, which describes how diet can impact gene expression and stability, should seek to provide recommendations on how to use diet to normalize gene expression for the purpose of reducing diseaseand aiding recovery from disease, as well as to promote continued good health for those who are disease free. J Nutrigenet Nutrigenomics. 2012;5(1):I-II. 84
  85. 85. What Would be an Ideal Nutritional- Chemotherapeutic Agent?It would be cytotoxic to cancer cells.It would be non-toxic to normal cells.It would be inexpensive and abundantlyavailable.It would literally be like the grass that grows inmy yard. Cell Signal. 2009 Nov;21(11):1541-7. 85
  86. 86. Taraxacum officinale: New Kid on the Block(?) The common name dandelion is from the French dent-de-lion, meaning "lions tooth".
  87. 87. Selective induction of apoptosis and autophagy through treatment with dandelion root extract in human pancreatic cancer cellsBxPC-3 and PANC-1 pancreatic cells weresensitive to aqueous DRE.This extract induces selective apoptosis in adose- and time-dependent manner. ● Dandelion root extract caused the collapse of the mitochondrial membrane potential, leading to prodeath autophagy. ● Normal human fibroblasts were resistant at similar doses.Pancreas. 2012 Oct;41(7):1039-47.
  88. 88. Efficient induction of extrinsic cell death by dandelion root extractDandelion Root Extract (DRE) is able toefficiently and selectively induce apoptosisand autophagy in human chronicmyelomonocytic leukemia in a dose and timedependent manner, with no significant toxicityon non-cancerous peripheral blood mononuclearcells.PLoS One. 2012;7(2):e30604.
  89. 89. The efficacy of dandelion root extract in inducing apoptosis in drug-resistant human melanoma cellsVarious natural compounds have shown efficacyin killing different cancers, albeit not alwaysspecifically. In this study, we show that dandelionroot extract (DRE) specifically and effectivelyinduces apoptosis in human melanoma cellswithout inducing toxicity in noncancerouscells. ● Therefore, treatment with this common, yet potent extract of natural compounds has proven novel in specifically inducing apoptosis in chemoresistant melanoma, without toxicity to healthy cells.Evid Based Complement Alternat Med. 2011;2011:129045.
  90. 90. Lupeol: Connotations for ChemopreventionThe perception of chemoprevention lies still in itsinfancy. Intervention, to slow down, arrest orreverse the process of carcinogenesis, by the useof either natural or synthetic substancesindividually or in combination therapy hasemerged as a promising and pragmatic medicalapproach to reduce cancer risk.This review asserts on the chemopreventive prospects of lupeoland reveals potential chemoprevention drug targets, central towhich are the cell cycle regulatory pathway genes and tries toexplain the mechanism operating behind its action.Cancer Lett. 2008 May 8;263(1):1-13.
  91. 91. Recommendations Eat the Dandelions Drink Dandelion TeaTake Dandelion Tinctures Bathe in DandelionsHave Dandelion Enemas
  92. 92. Dandelions are Weeds!Are You SURE they are Safe to Eat?
  93. 93. The soul should always stand ajar, readyto welcome the ecstatic experience.Emily Dickinson 93
  94. 94. A Formal Apology
  95. 95. Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators.Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive,anti-metastatic and pro-apoptotic in mostcancers, in vitro and in vivo in animals. ● They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, VEGF, NF-κB, p8, CHOP, TRB3 and pro- apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. inhibition ● They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on NF-kB transcription factors. factorsProg Lipid Res. 2012 Oct 26. pii: S0163-7827(12)00053-7.
  96. 96. Who Gives a Crap about Mary Jane?Cannabinoids as antioxidants and neuroprotectantsCannabinoids have been found to have antioxidant properties, unrelated to NMDAreceptor antagonism. This new found property makes cannabinoids useful in thetreatment and prophylaxis of wide variety of oxidation associated diseases, such asischemic, age-related, inflammatory and autoimmune diseases.Inventors: Hampson; Aidan J. (Irvine, CA), Axelrod; Julius (Rockville, MD), Grimaldi; Maurizio (Bethesda, MD)Assignee: The United States of America as represented by the Department of Health and Human Services(Washington, DC)Appl. No.: 09/674,028Filed: February 2, 2001PCT Filed: April 21, 1999PCT No.: PCT/US99/08769PCT Pub. No.: WO99/53917PCT Pub. Date: October 28, 1999
  97. 97.
  98. 98. What are Your Odds?Forty-two percent ofAmericans living todaycan expect to developcancer.Quillin, Patrick (2011-11-15). Beating Cancer with Nutrition: Optimal NutritionCan Improve Outcome inMedically-Treated Cancer Patients. (p. 53).BookMasters. Kindle Edition.
  99. 99. Chances of Survival is the Real Measure of SuccessGrouped together, theaverage cancer patienthas a 50/50 chance ofliving another 5 years,which are the sameodds he or she had in1971.Quillin, Patrick (2011-11-15). Beating Cancer with Nutrition: Optimal NutritionCan Improve Outcome inMedically-Treated Cancer Patients. (p. 52).BookMasters. Kindle Edition.
  100. 100. Cancer Drug ClaimsClaims for cancer drugs are generally based ontumor response rather than prolongation of life. Many tumors will initially shrink when chemo and radiation are applied, yet tumors often develop drug-resistance and are then unaffected by therapy. Quillin, Patrick (2011-11-15). Beating Cancer with Nutrition: Optimal Nutrition Can Improve Outcome in Medically-Treated Cancer Patients. (p. 53). BookMasters. Kindle Edition.
  101. 101. When the Real Work BeginsWhen the surgeon says,”We think we got it all.”--that is when the war oncancer must becomean invisible battleinvolving the patient’swell-nourished immunesystem.Quillin, Patrick (2011-11-15). Beating Cancer with Nutrition: Optimal NutritionCan Improve Outcome inMedically-Treated Cancer Patients. (p. 60).BookMasters. Kindle Edition.
  102. 102. Pancreatic CancerPancreatic cancer is thefourth leading causeof cancer death in thiscountry, and each year,~30,000 Americans dieof the disease.In this deadly disease,the mortality rateapproximately equalsthe incidence rate.American Cancer Society. Cancer figures and facts, 2004. Atlanta: AmericanCancer Society; 2004. 102
  103. 103. The antidote to exhaustion is not necessarily rest.The antidote to exhaustion is whole-heartedness. ~ David Steindl-Rast ~ 103
  104. 104. Cancer Biology 104
  105. 105. Growth of Cancer Cells  Cancer cells reproduce every 2-6 weeks. 2-6 weeks  Size of cancer cells:  One million cancer cells 2-6 weeks = head of a pin  One billion cancer cells = a small grape2-6 weeks  230 = 1,073,741,824 = 1 billion cells 2-6 weeks
  106. 106. Reconceptualizing Cancer Carcinogenesis is a multistep process that is activated by altered expression of transcriptional factors and proteinsinvolved in proliferation, cell cycle regulation, differentiation, apoptosis, angiogenesis, invasion and metastasis. Cancer Lett. 2008 Oct 8;269(2):352-62. 106
  107. 107. Deregulated Cell ProcessesDeregulated cell cycle progression and apoptosis together with increased angiogenic potential, invasion and metastasis have been described as hallmarks of cancer. Cancer Lett. 2008 Oct 8;269(2):352-62. 107
  108. 108. Conceptualizing a Nutritional Approach to CancerCell Cycle Controls ● Cyclins and Cyclin Dependent Kinases ● Tumor Suppressor ProteinsCell Signaling Controls ● Transcription Pathways ● Survival Pathways ● Death PathwaysGenetic and Epigenetic Controls ● Iron ● DNA Methylation 108
  109. 109. Cell Cycle Control Basics Managed by Cyclins and CDKSupervised by Tumor Suppressor Proteins Coordinated by Nutritional Signals The purpose of cell cycle processes is genetic transcription and expression. 109
  110. 110. The Cell Cycle e tid lo u ce tase b on du c Ri Re 110
  111. 111. Cell Cycle CheckpointsCell cycle checkpoints are control mechanismsthat ensure the fidelity of cell division ineukaryotic cells.Science. 1994 Dec 16;266(5192):1821-8.These checkpoints verify whether the processesat each phase of the cell cycle have beenaccurately completed before progression intothe next phase. ● G1/S Checkpoint ● G2 Checkpoint ● Metaphase Checkpoint 111
  112. 112. 112
  113. 113. Cyclin-CDK ComplexesCyclins are a family of proteins that control theprogression of cells through the cell cycle byactivating cyclin-dependent kinase (Cdk)enzymes.Oncogene. 2003 Aug 11;22(33):5208-19.G1/S Cyclins rise in late G1 and fall in early Sphase. The Cdk- G1/S cyclin complex begins toinduce the initial processes of DNA replication.PLoS One. 2012;7(1):e28568. 113
  114. 114. Transcription Activation P+Rb Cyclin D/ CDK 4/6 E2F M G1 Cyclin E/ CDK 2 Thymidine Kinase G2 S Iron + Dihydrofolate Ribonucleotide Reductase Reductase (DHFR)
  115. 115. Cell Cycle InhibitionExternal stimuli (i.e., The cip/waf familynutrients) and internal interacts with multiplesignals (i.e., DNA cyclin-CDK complexesdamage) regulate the and the INK4 familyformation of cyclin-CDK (p15, p16, p18, p19),complexes via cyclin- which specificallydependent kinase inhibits cyclin D-CDKinhibitors (CKI), which complexes.include the cip/waf Annu. Rev. Nutr. 2004. 24:433–53family (p21, p27, p57).Annu. Rev. Nutr. 2004. 24:433–53
  116. 116. Inhibitory Kinases Cyclin D/ CDK 4/6 INK4 p15, p16, p18, p19 M G1 Vitamin G2 S D3
  117. 117. Tumor Suppressor ProteinsA tumor suppressor protein which is coded for bya tumor suppressor gene is produced in responseto cellular stress: ● DNA damage ● Oxidative stress ● Osmotic shock ● RNA depletion ● Deregulated oncogene expression 117
  118. 118. How does P53 Function?Activated p53 binds DNA and activatesexpression of several genes including microRNA,WAF1/CIP1 encoding for p21 and hundreds ofother down-stream genes. ● p21 (WAF1) binds to the G1-S/CDK (CDK2) and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.Leukemia. 2009 Jun;23(6):1159-63 118
  119. 119. Some Examples of Tumor Suppressor GenesBRCA1BRCA2p16 (gene)p53 p63 p73 familyp21 p27 119
  120. 120. Tumor Suppressor Activity cip/waf Cyclin D/ p21, p27, p57 CDK 4/6 p53 M G1 Cyclin E/ Vitamin CDK 2 Vitamin A D3 G2 S DNA Damage
  121. 121. Why the Focus on Inhibitory Signaling? Cells have a Hunter-Gatherer beginning before they formed Communities of Cells.When the needs of the individual or community are not met, behaviors are changed in order to meet the perceived or real needs. Essentially, they pick up and leave.
  122. 122. ‡Nutrients that Exert a Chemoprotective and/orChemotherapeutic Effect Against Cancer byInfluencing: ● Cell Cycle Progression ● Apoptosis ● Metastasis ● Angiogenesis ‡ Some of the many, many, many nutrients in their unfractionated, whole and natural state. 122
  123. 123. Chemotherapeutic Agents are Natural ProductsThe overwhelming contribution of naturalproducts to the expansion of thechemotherapeutic arsenal is evidenced by the factthat 50% of all the anticancer drugs approvedworldwide between 1940 and 2006 were eithernatural products or natural product derived.J Nat Prod. 2007 Mar;70(3):461-77. 123
  124. 124. Targeted versus Multiparametric Approach Whereas pharmaceuticals have a targeted approach aimed at restoring health, diet is a multi- parametric approach to preserve and/or optimize health.FASEB J. 2005 Oct;19(12):1602-16.
  125. 125. Nutrition is Broad Spectrum The diet is comprised of a multitude of nutritional andchemical molecules each capable of regulating disparate biological processes, and thus cannot use an approach Similar to the pharmaceutical industry, i.e., the “one drug one target” paradigm. Curr Opin Biotechnol. 2001 Oct;12(5):516-22.
  126. 126. Retinoic Acid and PubMed.govCancer = 12487 Cancer =113 Cycle Arrest = 442 = 68 126
  127. 127. Retinoic Acid Inhibits Cell Cycle ProgressionCell cycle analysis indicates that retinoic acid(RA) inhibition of MCF-7 cell growth occursthrough induction of G1 arrest with a concomitantreduction in the proportion of cells in S and G2 +M phases. ● E2F1 promoter activity was reduced by 60%.Exp Cell Res. 1997 Aug 1;234(2):293-9 127
  128. 128. Retinoic Acid Enhances ApoptosisThe TRAIL receptor (TRAIL-R1; also known asdeath receptor 4) is a transmembrane receptorthat mediates TRAIL-induced apoptosis incancer cells. ● ATRA accentuates TRAIL-induced apoptosis, reveal a novel mechanism by which retinoids modulate apoptosis, and suggest a novel strategy to augment the anti-cancer activity of TRAIL.Cancer Res. 2011 Aug 1;71(15):5245-54.
  129. 129. Retinoic Acid, Collagenase and MetastasisInvasion and metastasis cause death of patientswith liver cancer. ● Type IV collagen is the main structure protein of basilar membrane which is a natural barrier for inhibiting the metastasis of liver cancer cells. All trans-retinoic acid (ATRA) to inhibits collagenase type IV in order to protect the type IV collagen and basilar membrane, to further suppress the metastasis of hepatocellular carcinomas.Hepatobiliary Pancreat Dis Int. 2004 Nov;3(4):588-90.
  130. 130. Retinoic Acid and AntiangiogenesisATRA can significantly inhibit tumor growth andhas anticancer effects on transplantable tumorgrowth of human ESCC cell line (esophageal squamous cancer cell)EC9706 in nude mice. ● These findings indicate that ATRA specifically down regulated VEGF and the components of VEGF signal transduction, which may be an important mechanism responsible for the neoangiogenesis inhibition of ESCC cells.Chin Med J (Engl). 2011 Sep;124(17):2708-14.
  131. 131. Retinoic Acid and Antioxidant Activity in Cancer CellsManganese superoxide dismutase mRNA,protein, and activity levels increased in a time-dependent manner upon treatment with ATRA. ● This study identifies SOD2 as a retinoid-responsive gene. ● These results suggest that signaling events involving NF- kappaB and SOD2 may contribute to the effects of retinoids used in cancer therapy.Free Radic Biol Med. 2008 Apr 15;44(8):1610-6.
  132. 132. Retinoids in Pancreatic CancerRetinoid treatment of pancreatic adenocarcinomaresults in inhibition of growth, induction ofcellular differentiation and decreasedadhesion to certain components of theextracellular matrix, all features compatible witha "less malignant" phenotype. ● In summary, these studies suggest that retinoids might be beneficial in the treatment of advanced pancreatic carcinoma patients based on their pleiotropic effects on tumor cell biology.Ann Oncol. 1999;10 Suppl 4:197-200. 132
  133. 133. Growth inhibitory effects of retinoic acid in human pancreatic cancer cellsRetinoids are potent growth inhibitory anddifferentiating agents in a variety of cancer celltypes.Retinoids induce growth arrest in all pancreaticcancer cell lines studied, regardless of their p53and differentiation status. ● Retinoic acid markedly inhibited proliferation of two cell lines (Capan-2 and Hs766T) in a concentration and time-dependent manner.Mol Cancer. 2007 Dec 24;6:82. 133
  134. 134. Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells.Acyclic retinoid (ACR), a new synthetic retinoid,9-cis-retinoic acid and gemcitabine preferentiallyinhibited the growth of human pancreatic cancercells (Panc-1 and KP-2) in comparison to normalhuman pancreatic epithelial cells. ● The combination of ACR plus gemcitabine synergistically inhibited the growth of Panc-1 cells.Cancer Lett. 2009 Jan 18;273(2):250-6. 134
  135. 135. If Retinoic Acid works all by itself,then why do we need a synthetic? 135
  136. 136. RecommendationsDont take preformedVitamin ATake provitamin A inthe form of mixedcarotenes.Seerecommendationsunder beta-caroteneand lycopene. 136
  137. 137. β-Carotene and PubMed.govCancer = 2718 Cancer = 59 Cycle Arrest = 16 = 854 137
  138. 138. Cell cycle regulation and induction of apoptosis by β-carotene in U937 and HL-60 leukemia cells.When [leukemic] cells were treated with 20microM of beta-carotene, total genomic DNAshowed a fragmentation pattern. ● Both the cell lines, on treatment with beta- carotene, showed a clear shift in G(1) phase of the cell cycle.J Biochem Mol Biol. 2007 Nov 30;40(6):1009-15 . 138
  139. 139. β-carotene apparently does it allBeta-carotene treatment significantly reduces thenumber of tumor-directed capillaries.Beta-carotene is able to inhibit proliferation,migration, and tube formation of endothelial cells. ● Beta-carotene treatment downregulates the expression of matrix metalloproteinase (MMP)-2, MMP-9, prolyl hydroxylase, and lysyl oxidase gene expression and upregulates the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2.Integr Cancer Ther. 2007 Sep;6(3):258-70. 139
  140. 140. RecommendationsDrink carrot juice as if itwere against the lawand until it turns yourskin orange.Supplements: Take onlysupplements containingmixed carotenes toobtain a broad spectrumof carotene activity. 140
  141. 141. 141
  142. 142. Lycopene and PubMed.govCancer = 947 Cancer = 12 Cycle Arrest = 17 = 251 142
  143. 143. Cell Cycle Arrest by LycopeneTomato consumption is associated withdecreased risk of prostate cancer.Lycopene increased the number of cells in theG(2)/M phase of the cell cycle and decreasedS-phase cells while no shifts in cell cycle weredetected in placebo-treated groups. ● Lycopene, therefore, deserves further study as a potential chemopreventive/chemotherapeutic agent.J Med Food. 2004 Fall;7(3):284-9.
  144. 144. Effect of lycopene on cell viability and cell cycle progression in human cancer cell lines.[The] data shows a significant decrease in thenumber of viable cells in three cancer cells lines (HT- after 48 h treatment with lycopene, and29, T84 and MCF-7)changes in the fraction of cells retained indifferent cell cycle phases. ● Lycopene promoted also cell cycle arrest followed by decreased cell viability in majority of cell lines after 96 h, as compared to controls. Furthermore, an increase in apoptosis was observed in four cell lines when cells were treated (T-84, HT-29, MCF-7 and DU145) with lycopene.Cancer Cell Int. 2012 Aug 6;12(1):36. 144
  145. 145. Lycopene Prevents MetastasisTumor metastasis is the most important cause ofcancer death.We showed that lycopene inhibited SK-Hep-1migration and invasion in a bell-shaped manner.Lycopene was much more effective than β-carotene in reducing cell invasion. ● We conclude that lycopene has significant antimigration and anti-invasion activity.J Nutr. 2005 Sep;135(9):2119-23.
  146. 146. Lycopene Inhibits AngiogenesisAngiogenesis is important for tumourvascularisation and growth, and is therefore apromising target for cancer therapy.The anti-angiogenic effects of lycopene in thepresent study were shown at a concentration thatshould be achievable by dietary means. ● These results extend our knowledge of one of the putative anti- cancer actions of lycopene.Br J Nutr. 2012 Aug;108(3):431-9.
  147. 147. Dietary intake of lycopene is associated with reduced pancreatic cancer risk462 histologically confirmed pancreatic cancercases and 4721 population-based controls werecompared to each other and against a self-adminstered dietary intake assessment. ● Lycopene, provided mainly by tomatoes, was associated with a 31% reduction in pancreatic cancer risk. ● The results of this study suggest that a diet rich in tomatoes and tomato-based products with high lycopene content may help reduce pancreatic cancer risk.J Nutr. 2005 Mar;135(3):592-7. 147
  148. 148. Lycopene YumminessLycopene is a bright red carotene and carotenoidpigment and phytochemical found in tomatoesand other red fruits and vegetables, such as redcarrots, red bell peppers, watermelons, andpapayas (but not strawberries or cherries).Although lycopene is chemically a carotene, it hasno vitamin A activity.J Am Coll Nutr October 2000 vol. 19 no. 5 563-569
  149. 149. RecommendationsEat and drink tomatobased foods until yourskin turns orange incolor provided yourenot allergic to tomatoes.Supplements: Takealgae or lycopenesupplements.
  150. 150.
  151. 151. Beware of ProgressThe federal government hassponsored research that has produced a tomato that is perfect in every respect, except that you cant eat it.We should make every effort to make sure this disease, often referred to as progress, doesnt spread.Andy Rooney 151
  152. 152. Vitamin D and PubMed.govCancer = 7123 Cancer =124 Cycle Arrest = 210 = 852 152
  153. 153. 1alpha,25-dihydroxyvitamin D3 induced cell cycle arrest at the G1-S checkpoint in ovarian cancer cells1,25(OH)(2)D(3) suppressed activation of theexternal signal regulated kinase by epidermalgrowth factors. ● Taken together, our studies demonstrate that 1,25(OH)(2)D(3) suppresses the response of human ovarian cancer cells to mitogenic growth factors and couple the suppression to the cell cycle arrest at G1-S checkpoint by the hormone.Mol Cell Endocrinol. 2011 May 16;338(1-2):58-67. 153
  154. 154. Vitamin D in Combination Cancer TreatmentCalcitriol elicits anti-tumor effects mainly throughthe induction of cancer cell apoptosis, cellcycle arrest, differentiation, angiogenesis andthe inhibition of cell invasiveness by a numberof mechanisms. ● Calcitriol enhances the cytotoxic effects of gamma irradiation and certain antioxidants and naturally derived compounds.J Cancer. 2010 Jul 15;1:101-7. 154
  155. 155. Vitamin D in Combination Cancer TreatmentCalcitriol potentiates the anti-tumor activities ofmultiple chemotherapeutics agents includingDNA-damaging agents cisplatin, carboplatin anddoxorubicin; antimetabolites 5-fluorouracil,cytarabine, hydroxyurea, cytarabine andgemcitabine; and microtubule-disturbing agentspaclitaxel and docetaxel.J Cancer. 2010 Jul 15;1:101-7. 155
  156. 156. Role of vitamin D in the prevention of pancreatic cancerVitamin D seems to have a protective effectagainst pancreatic cancer by participating innumerous proapoptotic, antiangiogenic, anti-inflammatory, prodifferentiating, andimmunomodulating mechanisms. ● Sun exposure has been associated with lower incidence of pancreatic cancer in ecological studies. ● Increased vitamin D levels seem to protect against pancreatic cancer, but caution is needed as excessive dietary intake may have opposite results.J Nutr Metab. 2010;2010:721365. 156
  157. 157. Recommendations Get a tan or go extinct. Take orally what your body can make with full body exposure at the MED*. Oral recommendations is between 10,000IU/day to 25,000IU/day.* Minimal Erythemal Dose 157
  158. 158. Are you positive that taking allthat Vitamin D is safe? 158
  159. 159. Curcumin and PubMed.govCancer = 1888 Cancer = 89 Cycle Arrest = 150 = 16 159
  160. 160. TurmericTurmeric (Curcuma longa) is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia. In medieval Europe, turmeric became known asIndian saffron since it was widely used as an alternative to the far more expensive saffron spice. The etymology of the word "turmeric" comes from the Latin "terra merita", literally "deserving earth".
  161. 161. Curcumin Induces Cell Cycle ArrestCurcumin induced successive G(1)/S andG(2)/M phase arrest in human osteosarcoma(HOS) cells. ● The G(1)/S and G(2)/S phase arrest was accompanied by down-regulation of cyclin D1, cdc2 and cyclin B1, respectively.Anticancer Res. 2009 Dec;29(12):5039-44.
  162. 162. Curcumin Inhibits MetastasisThe dietary antioxidant Curcumin has beenproposed for cancer chemoprevention since itinduces apoptosis and inhibits the formationof breast cancer metastases.Curcumin impairs transcription of CXCL1 and -2.This mitogenic chemokine silencing leads to downregulation of several metastasis-promoting genes. ● We therefore suggest that the decrease of CXCL1 and -2 mediated by Curcumin is involved in the inhibition of metastasis.Carcinogenesis. 2008 Apr;29(4):779-89.
  163. 163. Curcumin Suppresses Production of Matrix MetalloproteinaseProduction of MMP-1 and MMP-3 were inhibitedby curcumin in a dose-dependent manner. ● This study suggests that the suppression of MMP-1 and MMP-3 production by curcumin in CIA is mediated through the inhibition of PKCdelta and the JNK/c-Jun signaling pathway.J Pharmacol Sci. 2009 Sep;111(1):13-21.
  164. 164. Curcumin Blocks COX/LOX/PLAA variety of enzymes that are closely associatedwith inflammation and cancer were found to bemodulated by curcumin.These enzymes include COX-2, inducible nitricoxide synthase (iNOS), 5-LOX, andphospholipases A2 (PLA2). ● Curcumin exhibits an inhibitory effect on all of these proinflammatory enzymes.Curr Drug Targets. 2011 Mar 1;12(3):332-47.
  165. 165. Turmeric a Broad Spectrum Chemotherapeutic AgentTurmeric enhanced the production of ROS, andsuppressed the growth of tumor cell lines.Furthermore, turmeric sensitized the tumor cellsto chemotherapeutic agents capecitabine andtaxol.Turmeric was found to be more potent thanpure curcumin for cell growth inhibition.Turmeric also suppressed osteoclastogenesis.Mol Nutr Food Res. 2012 Mar;56(3):454-65.
  166. 166. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteersThe medicinal properties of curcumin obtainedfrom Curcuma longa L. cannot be utilisedbecause of poor bioavailability due to its rapidmetabolism in the liver and intestinal wall.Concomitant administration of piperineincreased bioavailability of curcumin by2000%. ● The study shows that piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.Planta Med. 1998 May;64(4):353-6.
  167. 167. RecommendationCook with turmeric, eatturmeric, drink tea madewith turmeric until yourbreath and your sweatcarries its odor.Mix it with your formulaand push it in throughyour GJ-Tube.Take it as tablets,capsules or tinctureswith piperine.
  168. 168. Cancer is somuch bigger than a TV show. Laura Linney
  169. 169.
  170. 170. Silymarin and PubMed.govCancer = 322 Cancer = 2 Cycle Arrest = 39 = 8 170
  171. 171. Milk Thistle: Silybum marianumMilk thistle is a thistle ofthe genus SilybumAdans., a floweringplant of the daisy family(Asteraceae).The plant is native tothe Mediterraneanregions of Europe,North Africa and theMiddle East.
  172. 172. [...] qui minor est inter omnes vos hic maior est (Luke 9:48 Vulgate)
  173. 173. Anticancer Res. 2006 Nov-Dec;26(6B):4457-98.
  174. 174. Silymarin/Silibinin cause G1 and G2-M cell cycle arrest in human prostate cancer PC3 cellsMolecular studies showed that G1 arrest wasassociated with a decrease in cyclin D1, cyclinD3, cyclin E, cyclin-dependent kinase (CDK)4,CDK6 and CDK2 protein levels, and CDK2 andCDK4 kinase activity, together with an increase inCDK inhibitors (CDKIs) Kip1/p27 and Cip1/p21.Oncogene. 2006 Feb 16;25(7):1053-69. 174
  175. 175. Silibinin Inhibits Cancer Cell GrowthRecent studies show that silibinin possesses astrong antineoplastic potential against manycancers.Silibinin treatment inhibited cell growth andtargeted cell-cycle progressing causing aprominent G(1) arrest. ● In mechanistic studies, silibinin modulated the protein levels of cyclin-dependent kinases (4, 6, and 2), cyclins (D1, D3, and E), CDKIs (p18/INK4C, p21/Cip1, and p27/Kip1).Mol Carcinog. 2010 Mar;49(3):247-58.
  176. 176. Silibinin Induces Cell-Cycle ArrestSilibinin, an effective anti-cancer andchemopreventive agent in various epithelialcancer models, has been reported to inhibitcancer cell growth in cervical cancer.Silibinin treatment of HeLa cells resulted in a G2arrest and induced a decrease in cyclin-dependent kinases involved in both G1 and G2progression. ● In addition, a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in cervical cancer.Cell Biochem Funct. 2012 Apr;30(3):243-8.
  177. 177. Silibinin Halts Cell Cycle ProgressionRecent studies have shown that silibinin inducesp21/Cip1 and p27/Kip1 and G1 arrest in differentprostate cancer cells irrespective of p53 status. ● Our results for the first time identify a central role of p21 and p27 induction and their regulatory mechanism in silibinin- mediated cell cycle arrest.Mol Cancer Ther. 2007 Oct;6(10):2696-707.
  178. 178. Silibinin Suppresses Growth of Human Colorectal Carcinoma (CRC)Silibinin treatment inhibited cell growth andinduced cell death.Silibinin also decreased cyclin-dependent kinase8 and cyclin C expression. ● Together, these findings suggest that silibinin inhibits the growth of CRC tumors and, therefore, could be an effective agent against CRC.Neoplasia. 2010 May;12(5):415-24.
  179. 179. Silymarin Inhibits Telomerase ActivityTelomerase is a selective target in cancer therapy.The treatment of the leukemia (K562) cells withsilymarin (a standardized mixture offlavonolignans) resulted in a significantinhibition of cell growth and telomeraseactivity. ● These results suggest a novel mechanism in the anticancer activity of silymarin in human leukemia K562 cells and may provide a basis for future development of anti-telomerase therapies.Planta Med. 2012 Jun;78(9):899-902.
  180. 180. Angiopreventive effect of Milk ThistleThe role of neo-angiogenesis in prostate cancer(PCA) growth and metastasis is well established.The oral feeding of these flavonolignanseffectively inhibited the growth of advancedhuman PCA (DU145) xenografts. ● These studies elucidated the comparative anti-angiogenic efficacy of pure flavonolignans from Milk Thistle and suggest their usefulness in PCA angioprevention.PLoS One. 2012;7(4):e34630.
  181. 181. Silymarin Blocks Migration/Invasion of Human Melanoma Cells.Metastatic melanoma is a leading cause of deathfrom skin diseases, and is often associated withactivation of Wnt/β-catenin signaling pathway.We found that treatment of human melanoma celllines with silymarin resulted in inhibition of cellmigration. ● These results indicate for the first time that silymarin inhibits melanoma cell migration by targeting β-catenin signaling pathway.PLoS One. 2011;6(7):e23000.
  182. 182. Recommendations Take Milk Thistle in all 4 forms: Liquid Extract Drink it as Tea Powdered Capsule Hard CapletesTitrate to nausea, then reduce below nausea.
  183. 183.
  184. 184. Genistein and PubMed.govCancer = 2328 Cancer = 55 Cycle Arrest = 174 = 99 184
  185. 185. Genistein on of Many IsoflavonesGenistein is one of several known isoflavones.Isoflavones, such as genistein and daidzein, arefound in a number of plants including lupin, favabeans, soybeans and coffee.J Agric Food Chem 41 (11): 1961–1967.J Altern Complement Med 3 (1): 7–12.J Agric Food Chem 58 (5): 3002–3007. 185
  186. 186. Genistein arrests cell cycle progression at G2-MGenistein inhibited in a dose-dependent mannerthe growth of HGC-27 cells derived from humangastric cancer.[A]nalysis showed that genistein almostcompletely arrested the cell cycle progressionat G2-M. ● This effect was reversible when genistein was removed from the culture medium.Cancer Res. 1993 Mar 15;53(6):1328-31. 186
  187. 187. Genistein Arrests Cell Cycle and Fosters ApoptosisThere is a growing body of experimental evidenceshowing that the inhibition of human cancer cellgrowth by genistein is mediated via themodulation of genes that are related to thecontrol of cell cycle and apoptosis. ● Genistein, one of the major soy isoflavones is a promising agent for cancer chemoprevention and further suggest that it could be an adjunct to cancer therapy by virtue of its effects on reversing radioresistance and chemoresistance.Cancer Lett. 2008 Oct 8;269(2):226-42. 187
  188. 188. Genistein Inhibits MetastasisConsumption of genistein in the diet has beenlinked to decreased rates of metastatic cancerin a number of population-based studies. ● At lower concentrations that are similar to those achieved through dietary consumption, genistein can inhibit the prometastatic processes of cancer cell detachment, migration, and invasion through a variety of mechanisms.Cancer Metastasis Rev. 2010 Sep;29(3):465-82. 188
  189. 189. A novel approach to gemcitabine-resistant pancreatic cancer cells in vitro and in vivoGenistein pretreatment together with lowconcentration of Oxaliplatin (OxP) showedsignificant reduction in cell viability and colonyformation concomitant with increased apoptosis (p< 0.01), which was highly synergistic. ● From these results, we conclude that genistein sensitizes drug-resistant PC to OxP resulting in greater antitumor effects, and thus our data suggest that this approach could be useful in improving the treatment outcome for patients diagnosed with PC.Int J Cancer. 2011 Mar 1;128(5):1240-50. 189
  190. 190. Recommendation Eat Fava Beans. Watch a movie and snack on non-GMO Edemame.Put it in your childrens lunch box. Invent a way to turn fava beans Into snack chips. 190
  191. 191. 191
  192. 192. EGCG and PubMed.govCancer = 1022 Cancer = 22 Cycle Arrest = 83 = 21 192
  193. 193. Green TeaA green tea extract is a herbal derivative from green tea leaves (Camellia sinensis). Containing antioxidant ingredients – mainly green tea catechins (GTC) – green tea and its derivatives.
  194. 194. Epigallocatechin GallateEGCG is the mostabundant catechin intea and is a potentantioxidant that mayhave therapeuticapplications in thetreatment of manydisorders (e.g. cancer).It is found in green teabut not black tea.
  195. 195. EGCG Induces Cell ProliferationThe EGCG treated human ovarian cancer line,SKOV-3 cells showed inhibition of cell viability andproliferation in a dose-dependent manner. ● In SKOV-3 cells, EGCG inhibits cell proliferation via DNA synthesis reduction and induces apoptotic cell death via DNA damage, thus elucidating a novel, plausible mechanism of EGCG anti-tumorigenic property.Anticancer Res. 2010 Jul;30(7):2519-23.
  196. 196. EGCG Reduces MetastasisTumor metastasis is the main obstacle to thetreatment of lung cancer. ● This study showed that epigallocatechin-3-gallate (EGCG), a natural polyphenol in green tea, is a potent inhibitor of MMP-2 expression. ● EGCG effectively suppressed the invasion and migration of highly invasive CL1-5 lung cancer cells.J Agric Food Chem. 2011 Dec 28;59(24):13318-27.
  197. 197. Antimetastatic Effect of EGCGMetastasis is one of the major causes of mortalityin bladder cancer patients.Mechanistically, EGCG inhibited [...] theexpression of matrix metalloproteinase-9(MMP-9), ultimately suppressing invasion andmetastasis. ● These findings suggest that EGCG is a potential therapeutic candidate against tumor invasion.Mol Med Report. 2012 Nov;6(5):1040-4.
  198. 198. EGCG Decreases Angiogenetic PotentialRecently, EGCG was found to decrease VEGFreceptor phosphorylation and induces apoptosisin chronic lymphocytic leukemia B cells.Leukemia. 2005 Apr;19(4):513-23.[T]he inhibition of VEGF binding to its receptormay contribute to the antiangiogenic and cancerchemopreventive effects of EGCG.Cancer Res 66: 2500-2505, 2006.
  199. 199. EGCG Blocks COXIt has been shown that EGCG reduced theprotein expression and activity of COX-2following interleukin-1h stimulation of humanchondrocytes. ● Most research findings strongly suggest that development of chemopreventive compounds, which can block COX-2 expression preferably without affecting COX-1, is a high priority for cancer research.Cancer Res 66: 2500-2505, 2006.
  200. 200. EGCG enhances the therapeutic potential of gemcitabine in human pancreatic cancer.The effects of epigallocathechin gallate (EGCG) inpancreatic cancer cells were assessed withgemcitabine for the treatment and/or prevention ofpancreatic cancer. ● EGCG inhibited cell motility, migration and invasion ● Gemcitabine synergized with EGCG to inhibit cell viability and induce apoptosis in pancreatic cancer cells.PLoS One. 2012;7(2):e31067. 200
  201. 201. Recommendations Drink Green Tea Use Green Tea TincturesTake Green Tea Supplements Eat Green Tea Ice cream Have Green Tea Enemas Take Green Tea Baths 201
  202. 202. 202
  203. 203. Resveratrol and PubMed.govCancer = 1561 Cancer = 41 Cycle Arrest = 147 = 13 203
  204. 204. 204ANTICANCER RESEARCH 24: 2783-2840 (2004)
  205. 205. 205ANTICANCER RESEARCH 24: 2783-2840 (2004)
  206. 206. Resveratrol inhibits cell growth by inducing cell cycle arrest in activated hepatic stellate cellsResveratrol (RSV) exerts anti-proliferative andpro-apoptotic actions in different cell lines.RSV induced an increase in the number of[hepatic cancer] cells in the S- and sub-G1phases. ● It is notable that these RSV actions are mediated at nanomolar levels, compatible with the concentrations of free RSV in biological fluids after ingestion of polyphenol-rich foods, suggesting a possible effect of these foods as an adjuvant treatment in chronic liver diseases.Mol Cell Biochem. 2008 Aug;315(1-2):1-7. 206
  207. 207. Multiple molecular Targets of Resveratrol: Anti-carcinogenic MechanismsExtensive in vitro studies revealed multipleintracellular targets of resveratrol, which affectcell growth, inflammation, apoptosis,angiogenesis, and invasion and metastasis. ● These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases; transcription factors NF-kappaB; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators.Arch Biochem Biophys. 2009 Jun 15;486(2):95-102 . 207
  208. 208. Resveratrol Inhibits MetastasisAfter resveratrol treatment, cell adhesion,wound migration, invasion, and MMP-9 activitywere significantly decreased in a dose-dependent manner in 4T1 cells (P < (metastatic breast cancer)0.05). ● The numbers of pulmonary nodules were significantly decreased in mice fed the resveratrol (P < 0.05). ● The plasma MMP-9 activity was decreased in response to treatment with resveratrol in mice (P < 0.05). ● We conclude that resveratrol inhibits cancer metastasis both in vitro and in vivo, and this inhibition is likely due to the decrease in MMP-9 activity caused by resveratrol.Nutr Res Pract. 2012 Aug;6(4):294-300. 208
  209. 209. Resveratrol Blocks LTA4 Hydroxylase in Pancreatic Cancer cellsResveratrol directly bound to leukotriene A(4)hydrolase (LTA(4)H) in vitro and in cells andsuppressed proliferation and growth ofpancreatic cancer by inhibiting LTB(4)production and expression of the LTB(4)receptor 1 (BLT(1)). ● Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA(4)H activity. ● Our findings identify LTA(4)H as a functionally important target for mediating the anticancer properties of resveratrol.Cancer Res. 2010 Dec 1;70(23):9755-64. 209
  210. 210. Resveratrol inhibits proliferation and induces apoptosis in pancreatic cancer cellResveratrol inhibited the growth of pancreaticcancer cells in a dose- and time-dependentmanner. ● Compared with control group, the cells in the G0/G1 phase and the apoptosis rate were significantly increased.Pancreatology. 2011;11(6):601-9. 210
  211. 211. Resveratrol enhances antitumor activity of gemcitabine in human pancreatic cancerNew agents that are safe and effective are highlyneeded.Resveratrol is one such agent which is safe andmultitargeted; and has been linked withsuppression of survival, proliferation, invasionand angiogenesis of cancer. ● Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expression of bcl-2, bcl-xL, COX-2, cyclin D1 MMP-9 and VEGF.Int J Cancer. 2010 Jul 15;127(2):257-68. 211
  212. 212. Resveratrol enhances antitumor activity of gemcitabine in human pancreatic cancerIn an orthotopic model of human PaCa, we foundthat resveratrol significantly suppressed thegrowth of the tumor (p < 0.001) and this effectwas further enhanced by gemcitabine (p < 0.001). ● As compared to vehicle control, resveratrol also suppressed the NF-kappaB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9 and survivin. Overall our results demonstrate that resveratrol can potentiate the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis.Int J Cancer. 2010 Jul 15;127(2):257-68. 212
  213. 213. RecommendationsEat grapes, raisins, cranberries, blueberries, blackberries, raspberries, goji berries, frankenberries, matthiasberries, manfrediberries ... Drink red wines, fresh juicesBathe in it, wash with it, use it as an enema. Take Resveratrol Supplements 213
  214. 214. 214
  215. 215. Indole-3-Carbinol and PubMed.govCancer = 436 Cancer = 8 Cycle Arrest = 48 = 10 215
  216. 216. Cell Cycle Arrest by I3CIndole-3-carbinol (I3C), a compound that occursnaturally in Brassica vegetables such as cabbageand broccoli, can induce a G1 cell-cycle arrestof human MCF-7 breast cancer cells that isaccompanied by the selective inhibition ofcyclin-dependent kinase 6 (Cdk6) expressionand stimulation of p21(Waf1/Cip1) geneexpression.J Nutr. 2003 Jul;133(7 Suppl):2448S-2455S. 216
  217. 217. I3C Inhibits MetastasisI3C elicited a significant inhibition of in vitrocell adhesion, migration, and invasion as wellas in vivo lung metastasis.I3C also suppressed the 17beta-estradiolstimulated migration and invasion in estrogen-responsive MCF-7 cells. ● I3C significantly caused a dose-dependent increase in BRCA1 expression. ● Clinical application of I3C may contribute to the potential benefit for suppression of breast cancer invasion and metastasis.J Mol Med (Berl). 2000;78(3):155-65. 217
  218. 218. Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cellsIndole-3-carbinol (I3C) induces a G1 growtharrest of human reproductive cancer cells. ● We previously reported that in LNCaP prostate cancer cells, I3C down-regulated cyclin-dependent kinase (CDK) 2 activity.I3C increased the level of activated p53 nuclearprotein that is competent to bind its DNA targetsite on the p21 promoter.Biochem Pharmacol. 2006 Dec 15;72(12):1714-23. 218
  219. 219. RecommendationsEat, eat, eat them until your urine and yourpooh smells like cabbage or broccoli.Take I3C and DIM supplementsUse the pot liquor to bathe wounds and as anenemaMake poultices to care for wounds it them 219
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