Mel Litman MD Weston Price Foundation Baltimore Nov 18 2018 Incidence of Cancer in America CACancer Journal for Clinicians 2000 19003 of deaths from cancer 200024 of deaths from cancer ID: 775618
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Slide1
Integrative Cancer Treatment
Mel
Litman
MD
Weston Price Foundation, Baltimore
Nov 18, 2018
Slide2Incidence of Cancer in AmericaCA,Cancer Journal for Clinicians, 2000
1900-3% of deaths from cancer
2000-24% of deaths from cancer
(surpassing heart disease as #1 cause)
28% increase in childhood cancers from 1950 to 1987
Slide3Breast Cancer Incidence in U.S.Surveillance Epidemiology and End Results SEER 2006
1940—50/100,000
2000—140/100,000
----------------------------------------------------------------
Between 1975 and 1994:
Cancer in women increased by 1.6% per year
Cancer in men increased by 1.5% per year
(Annual Review of Public Health 1999)
Slide4Cancer Incidence in Five Continents, 1982
Breast cancer among Chinese women living in China (age 45-75 yrs)—40-60/100,000
Breast cancer among Chinese women living in San Francisco(age 45-75 yrs)—150-160/100,000
Slide5PROGRESS AGAINST CANCER?
NEJM, 1986
Review of the overall progress against cancer during the years 1950-1982 in the U.S.
Statistics showing increases in both the incidence and mortality rates of cancer.
Follow-up paper in same journal in 1997 concluded that the overall death rate for cancer was 2.7% higher in 1994 than in 1982.
The main declines in mortality in specific cancers occurred in cancer of the cervix and colon (mainly attributed to better screening of precancerous lesions) and in lung cancer due to decreased smoking
Slide6The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies
Clin
Oncol
2004
Review of clinical trials reporting 5 year survival benefit attributed to
cytotoxic
chemotherapy for 22 major adult malignancies in U.S. and Australia.
“The overall contribution of curative and adjuvant
cytotoxic
chemotherapy to 5-yr survival in adults was estimated to be 2.3% in Australia and 2.1% in the USA…it is clear that
cytotoxic
chemotherapy only makes a minor contribution to cancer survival.”
Slide7Serum B-vitamins and risk of lung cancer
JAMA 2010
Survey of 385,000 people in Europe.
High levels of B6 or
Folate
or
Methionine
associated with a 50% or greater reduction in lung cancer.
Greater reduction if all were at good levels.
Slide8Dietary supplements and mortality rate in older women
Arch Intern Med 2011 The Iowa Women’s Health
Study
Reported: “Multivitamins increase deaths in older women”
Study findings: B-complex vitamins associated with 7% decrease in mortality.
Vit
C associated with a 4% decrease in mortality.
Vit
D associated with a 8% decrease in mortality. Various minerals associated with a decrease in mortality.
Slide9Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg)
European Journal of Nutrition 2012
23,943 participants followed for average of 11 years.
Baseline users of antioxidant supplements had a significantly reduced risk of cancer mortality (48% less)
Slide10EPIC-Heidelberg (cont.)
All cause mortality 42% less compared to never-users.
But—non-users at baseline who started supplements during the follow-up period had increased risks of cancer and all-cause mortality.
Authors suggest a “sick-user effect”
eg
. People who start supplements ‘because’ they become ill.
Slide11Long-term, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle Cohort
J
Clin
Oncol
, 2017, Oct
Study looking at use of supplements and cancer risk
Reported increased risk with use of individual supplements of B12 and B6, but not when part of a multivitamin
But—no stratification for ‘sick-user effect’
---no indication of blood levels,
eg
. B12 supplement often taken for B12 deficiency due to malabsorption and may still be deficient with an oral supplement
Slide12Multivitamins in the Prevention of Cancer in Men. The Physicians’ Health Study II Randomized Control Trial
JAMA 2012
Large
randomi
z
ed
, double-blind, placebo-controlled trial.
14,641 male US physicians 50
yrs
or older
Followed for average of 11 years. Randomized to either multivitamin or placebo.
Statistically significant reduction of about 8% in total cancer incidence in men taking daily multivitamin.
Slide13Megadose vitamin in bladder cancer
J
Urol
1994
65 patients with bladder cancer randomized to either RDA multivitamin or RDA
vit
+
Vit
A 40,000
iu
, B6 100 mg,
Vit
C 2000 mg,
Vit
E 400
iu
, Zinc 90 mg
After 10 months—80% of RDA supplement group relapsed. ---40% of “megavitamin” group relapsed.
Slide14Vitamin D for cancer prevention: global perspective.
Ann
Epidemiol
2009
Based on observational studies and a randomized clinical trial.
Expected effect of raising year-round serum
Vit
D to 40-60
ng
/dl—reduced case-fatality rate of patients with breast, colorectal, prostate cancer by half. Generally needing 4000-5000
iu
per day to achieve levels.
Slide15Lifestyle influences on cancer regression
Int
J
Biosoc
Res, 1988
200 people reporting “spontaneous regression” in cancer : 87% made major dietary changes, 65% used nutritional supplements, 55% used a form of detoxification
Slide16Antioxidants and breast cancer risk-a population-based case-control study in Canada
BMC Cancer, 2011
Comparison of antioxidant intake of 10 yrs or more in 2,362 cases with breast cancer compared to 2,496 controls
Results: Breast cancer risk in premenopausal women reduced by 54% in women using zinc supplementation. Breast cancer risk in postmenopausal women reduced 26% with multivitamin, 42% with beta-carotene, 21% with vitamin C, 25% with vitamin E, and 53% with zinc
Slide17Shanghai breast cancer survival study
Cancer Epidemiology, Biomarkers, & Prevention, 2011
Prospective cohort study of women receiving conventional cancer treatment +/- nutritional supplements in the 1
st
6 months after diagnosis
4877 women aged 20-75 yrs with breast cancer
Women who used
vit
E,
vit
C, or multivitamins had 18% reduced risk of death and 22% decreased risk of recurrence
Slide18San Antonio Breast Cancer Symposium, Dec 2010
2239 women diagnosed with early stage breast cancer
Results: women who had continually taken multivitamins with minerals before diagnosis and continued after were 31% less likely to have a recurrence; 47% less likely to die of breast cancer; and 27% less likely to die of any cause
Less clear benefit if women took only vitamins without minerals
Slide19Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism
Science Translational Medicine, 2017
Breast cancer cells spread through sites in tumors called Tumor Microenvironment of Metastasis (TMEM)
Residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide showed increased TMEM scores, ‘suggesting that chemotherapy, despite decreasing tumor size, increased the risk of metastatic dissemination’.
Slide20Women’s Health Initiative
JAMA 2001
HRT with
Premarin
/Provera
Breast cancer increased by 26%
CVD, stroke, blood clots increased.
Discussion
“It remains possible that transdermal estradiol with progesterone, which more closely mimics the normal physiology and metabolism of endogenous sex hormones may provide a different risk-benefit profile.” Writing Group for WHI
Slide21Women’s Health Initiative
JAMA 2011
Breast cancer
reduced
20-27% in
Premarin
only group
Also reductions in heart disease and all-cause mortality
Eliminating synthetic progestin eliminated risks
Slide22The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model
ReprodBiolEndocinol
2014, 12:66
Breast cancer implanted in mice
Divided into 8 groups to test a variety of combinations of aromatase inhibitor, estradiol, progesterone, and testosterone
Results:
Placebo and low dose estradiol + progesterone had fastest growth
1) AI or 2) high dose estradiol + progesterone or 3) AI + estradiol + progesterone. All 3 groups had about an equal modest reduction in growth
Slide23ReprodBiolEndocrinol (cont.)
Estradiol + Progesterone + Testosterone had most significant reduction in tumor growth
Measures of lipids, bone metabolism and memory all worse in AI groups
After active phase of treatment with AI (drug stopped), tumor growth accelerated
Slide24Fifteen-year effects of H pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality
J
Natl
Can Inst 2012
3365 subjects randomized control trial
Approximately 50% reduction in deaths from gastric and esophageal cancer in those taking “vitamin treatment” (
vit
C, E, selenium)
Slide25Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with lung cancer
Anticancer Res, 1992
18 patients with small cell lung cancer receiving standard therapy, given multiple high-dose vitamins and minerals
Expected survival at 30 months—1%
8/18 (40%) alive at 6 yrs
Improved chances if starting antioxidants earlier
Slide26Chemotherapy alone vs chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer
J Am
Coll
Nutr
2005
136 patients with stage 3-4 NSCLC randomized to chemotherapy or chemo plus oral
Vit
C,
Vit
E, beta-carotene.
Results: -chemotherapy alone RR 33%, no CR
-survival at 1 yr 32.9%
-chemo + antioxidants RR 37%, CR in 2 patients -survival at 1 yr 39.1%
Slide27Chemoprevention of DNBA-induced mammary carcinogenesis in rats
Jpn
J Ca Res, 1990
Rats given DNBA (carcinogen)—100% developed cancer
Added nutrients—selenium, magnesium,
vit
C,
vit
A alone or in combinations
Results: 1 nutrient-about 50% decrease in cancer
2 nutrients-about 70% decrease
3 nutrients-about 80% decrease
4 nutrients-about 88% decrease
Slide28Vit C and K3
Cancer, 1989
Each vitamin shown to have anti-cancer activity individually on cultured breast cancer cell lines
Combined vitamins are effective at 10-50 times lower dosages
Slide29The effect if vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers
NEJM, 1994
Alpha
tocopherol
(50mg) or beta carotene or both or placebo given to 29,133 male smokers
Results: no effect of
vit
E
18% increase in lung cancer in beta carotene group
Slide30Antioxidants/Free Radicals
Over 200 epidemiology studies showing fruits &vegetables (high antioxidants) lower cancer risk.11 studies showing beta carotene protective against lung cancer
Research showing isolated antioxidants can become free radicals in environment high in free radicals
eg
. Smoking
Antioxidants work as ‘teams’ physiologically
Slide31Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients
Int J Cancer 2006Head and neck cancer patients treated with radiation-given either synthetic beta carotene 30mg (discontinued during study) and/or alpha-tocopherol (vit E) 400 iu or placebo
Results: 40% higher early recurrence of cancer in supplement group
No difference between the groups after 8 yrs of follow-up
Slide32Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: A randomized trial among head and neck cancer patients
Int
J Cancer, 2007
Increased cancer recurrence only occurred in patients smoking during their radiation treatments.
No increases at all in those not smoking.
Significant decreased side effects (tissue damage) from the radiation in antioxidant group.
Slide33Rationale for using high-dose multiple antioxidants as an adjunct to radiation therapy and chemotherapy
J
Nutr
, 2004, Prasad
“Laboratory data show that antioxidants protect cancer cells when administered only one at a time at low doses”
“A mixture of
vit
A, E
succinate
,
vit
C, and
carotenoids
produces about 50% proliferation inhibition in human melanoma cells in culture at doses that do not reduce proliferation when used individually. Doubling only the dose of
vit
C in the mixture causes about 90% proliferation inhibition”
Slide34Prasad, 2004 (cont)
“
Vit
A and beta carotene at high doses administered daily before radiation and during the entire observation period produces more than 90% cure rate in mice with transplanted breast
adenocarcinoma
; whereas treatment with radiation alone or antioxidant alone is ineffective
Slide35Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival
Alt
Ther
Health Med, 2007, Simone C
280 peer reviewed studies
50 human clinical trials (various nutrients in combination with standard treatments)
“Furthermore, they enhance the killing of therapeutic modalities for cancer, decrease their side effects and protect normal tissue”
Slide36Impact of antioxidant supplementation on chemotherapeutic efficacy: A systematic review of the evidence from randomised controlled trials
Cancer Treat Rev, 2007, Block K
Reviewed 845 peer-reviewed articles
19 clinical trials meeting strict criteria
Conclusion: None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many studies showed increased survival times, increased tumor responses or both as well as fewer toxicities than controls.
Slide37Neuroprotective effect of glutathione on oxaplatin-based chemotherapy in advanced colorectal cancer
J
Clin
Oncol
2002
52 patients with advanced colorectal cancer randomized to receive
oxaplatin
with IV glutathione or saline pretreatment
Results: neuropathy occurred in 42% of control group and 27% of glutathione group
Slide38Neuroprotective effect of vit E supplementation in patients treated with cisplatin chemotherapy
J
Clin
Oncol
27 patients with various cancers treated with
cisplatin
alone or with added
vit
E 300
iu
Results: more than 85% of
cisplatin
group developed neuropathy, 31% of
vit
E group developed nerve damage. Severity of damage was also lower in
vit
E group.
Slide39Antioxidants and chemotherapy toxicity
A number of other clinical trials with various antioxidants showing decreases in
neurotoxity
,
cardiotoxicity
, lung damage,
mucositis
, bone marrow toxicity
No trials reporting decreased efficacy of chemotherapy
Slide40The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer
J Am
Coll
Nutr
2003
2 cases of advanced ovarian cancer (stage 3)
Had standard chemotherapy
Taking high dose oral antioxidants
Given intravenous vitamin C twice per wk
Both patients showing no evidence of disease over 3 yrs later
Slide41Intravenously administered vitamin C as cancer therapy: three cases
CMAJ 2006
3 cases of confirmed cancer treated with intravenous
vit
C and supplements (declined chemotherapy)
Showed unexpectedly long survival times, with one apparent cure
Slide42Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo/radiotherapy and aftercare
In Vivo 2011
125 breast cancer patients. All received standard care.
53 received additional IVC for at least 4 wks
Results: IVC administration resulted in a
signif
reduction in symptoms of nausea, loss of appetite, fatigue, depression, sleep disorders, dizziness, hemorrhagic diathesis
Slide43Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs
Cancer Res 2008
Effect of pre-treatment with
dehydroascorbic
acid (oxidized
ascorbate
) on the
cytotoxicity
of doxorubicin,
cisplatin
,
vincristine
,
methotrexate
, and
imatinib
on a cell line of leukemia and lymphoma
Showed a decrease in
cytotoxicity
of all drugs tested
Slide44Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs
Cancer
ChemotherPharmacol
2011
Investigating the effects of both
ascorbate
and
dehydroascorbate
, with and without various chemotherapeutic drugs, on cancer cell lines.
Conclusions: “higher therapeutic efficacy of
ascorbate
over
dihydro-ascorbate
for various cell lines”
“
ascorbate
shows therapeutic efficacy in tumor cells”
CancerChemotherPharmacol 2011 (cont)
“in addition to the induction of apoptosis, also include an
antiproliferative
effect by inducing cell cycle arrest”
“Furthermore, ascorbate treatment specifically enhances the cytostatic potency of certain chemotherapeutics (neutral effect on others), which implicates therapeutic benefit during tumor treatment”
Slide46Vitamin C and survival among women with breast cancer: a meta-analysis
Eur
J Cancer 2014
Meta-analysis of 10 prospective studies using either
vit
c supplement or increased dietary sources, post-diagnosis—included over 17,000 women with breast cancer.
Results: 19% decreased total deaths with
vit
c supplement
27% decreased deaths with dietary increase of 100 mg
vit
c
Slide47High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy
Sci
Transl
Med 2014
“Combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer”…”no toxicity to liver, kidney or spleen”
Slide48“Evidence-based Medicine
Story reported in New Zealand in 2010 of farmer with swine flu. Hospitalized, in coma, considered terminal. Family insisted on trying IV
vit
C as last hope. Physicians at hospital refused on the grounds that it was unscientific and irrational (“no evidence”).
Family went to court to allow treatment and won. Patient given
vit
C and made a full recovery.
Slide49Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient
Society of Critical Care Medicine (SCCM) and
American Society for Parental and Enteral Nutrition (ASPEN)
2009 recommendation that high-dose intravenous antioxidant therapy for all critically ill patients.
Based on systematic review of studies which included use of IV
vit
C 1gm every 8 hrs and other antioxidants showing improved clinical outcomes of critically ill patients.
Slide50High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trial
PLOS ONE 2015
Small clinical trial in advanced cancer patients either determined to be unlikely to respond to further chemotherapy
Given high dose intravenous vitamin c along with a selected chemotherapy
Results showed ½ of the patients showed no benefit of treatment, while ½ experienced either transient stable disease or longer-lasting but impermanent stable disease. No significant toxicity of vitamin c noted
Conclusions from paper: “The present state of chemotherapy is unsatisfactory. New cancer drugs continue to be developed and approved on the basis of marginal improvements in survival at an unsustainably high financial cost. It would seem more rational for cancer investigators to attempt to improve the effectiveness of well-known, inexpensive generic cancer chemotherapies by studying their clinical interactions with antioxidants, especially vitamin c.” “Despite its biological and clinical plausibility, it is ignored by conventional cancer investigators and funding agencies “
Slide51Vitamin C Deficiency in a University Teaching Hospital
JAmCollNutr
2007
60% of hospitalized patients in a Canadian teaching hospital had a sub-normal
vit
C concentration in their blood shortly after admission
Level remained unimproved after an average of 17 days in hospital
“Conclusion: Vitamin C deficiency is prevalent and sustained in patients in a Canadian teaching hospital”
Slide52Tumors: Wounds that do not heal: Similarities between tumor stroma generation and wound healing
NEJM, 1986
Cancer uses normal mechanisms of healing an injury in an abnormal way.
Creates inflammation, growth factors, enzymes,
angiogenic
chemicals
But without an “off switch”
Slide53The Cancer Terrain
The body’s influence on tumor promotion:
Increased oxidation—free radicals
Inflammation
Immune system failure
Glycemia
—high blood sugar, high insulin (insulin resistance)
Stress hormones—immune suppression
--inflammation
Slide54Mechanisms Targeted by Chemopreventive Agents
Slide55Pro-Cancer Events
John
Boik
Induction of genetic instability-allowing mutations
Abnormal expression of genes.
Abnormal signal transduction.
Abnormal cell-to-cell communication.
Induction of angiogenesis
Invasion and metastasis.
Immune evasion.
Slide56Therapeutic Goals
Reduce genetic instability
eg
. Oxidative stress
Inhibit abnormal expression of genes—modify transcription factors that turn genes on and off.
Inhibit abnormal signal transduction—block signals giving undesired messages to the cell
eg
. For proliferation.
Encourage normal cell-to-cell communication
eg
. Improve response of cancer cell to regulating signals from normal cells.
Inhibit angiogenesis—normalize factors that stimulate angiogenesis
Inhibit invasion and metastasis—inhibit enzymes that digest tissue and that allow cancer cells to move.
Increase immune response—increase/activate immune cells and decrease ability of cancer cells to ‘hide’.
Slide57End of cancer-genome project prompts rethink
Nature 2015
Began 2006 to genetically profile 10,000
tumours
.
Discovered nearly 10 million cancer-related mutations at a cost of almost $400 million
“…most of the mutations formed a bewildering hodgepodge of genetic oddities, with little commonality between
tumours
.
“…cancers are often quick to become resistant, typically activating different genes to bypass whatever cellular process is blocked by the treatment”
Slide58On the origin of Cancer Cell [Otto Warburg]
Science 1956
Cancer arises from damage to cellular respiration
Energy through fermentation gradually compensates for insufficient respiration
Cancer cells continue to ferment lactate in presence of oxygen---’Warburg Effect’
Metabolic signature of cancer cells
Slide59Cancer as a metabolic disease
Nutrition & Metabolism 2010 [
Seyfried
]
“Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cell origin”…”general hypothesis that genomic instability and essentially all hallmarks of cancer including aerobic glycolysis (Warburg effect) can be linked to impaired mitochondrial function and energy metabolism”
Slide60Cytoplasmic suppression of malignancy
In Vitro Cell Dev Biol, 1987Nucleus from cancer cell (containing ‘cancer DNA’) Transferred to cytoplasm of normal cell Extinguishes tumorigenic phenotype (behaves as normal cell)
Slide61Cytoplasmic suppression of tumorigenicity in reconstructed mouse cells
Cancer Res, 1988
Repeat of experiment at different research center with added precautions to reduce possible confounding factors.
Produced the same result of eliminating expression of cancer behavior with effects of normal cytoplasm.
Slide62Cytoplasmic mediation of malignancy
In Vitro Cell Dev Biol, 1988Nucleus from normal cell (no ‘cancer genes’) Transferred to cytoplasm of cancer cell Cancer cell
Slide63Retrograde regulation due to mitochondrial dysfunction may be an important mechanism for carcinogenesis
Med Hypothesis 2005
Signaling pathways from dysfunctional mitochondria to the nucleus can affect cellular metabolism, proliferation, tumor progression, metastasis, resistance to apoptosis.
Slide64Cancer Stem Cell Theory and the Warburg Effect, Two Sides of the Same Coin?
Int
J
Mol
Sci
2014
Two theories challenging the paradigm of the past 50
yrs
—cancer originating from multiple genetic mutations
Cancer Stem Cell Theory. Cells capable of initiating, promoting and spreading neoplastic growths, while other tumour cells not able to initiate new tumours. Generally not killed by conventional cytotoxic therapies, therefore, not eliminating the disease
Metabolic Theory of Cancer (Warburg). Typical shift in metabolism (glycolysis) seen in cancer cells
Question of cancer stem cells displaying metabolic changes or damaged metabolism promoting ‘stem-like’ changes
Future directions in therapy to address the cancer stem cells/metabolism as way of actually eliminating the disease
Slide65Is there a role for carbohydrate restriction in the treatment and prevention of cancer
Nutrition & Metabolism 2011
“Most malignant cells depend on steady glucose availability for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction”
Slide66Carbohydrate restriction (cont.)
“High insulin and IGF-1 levels resulting from chronic ingestion of carbohydrate-rich Western diet meals can directly promote tumor proliferation”
“Ketone bodies that are elevated when insulin and blood glucose levels are low have been found to negatively affect proliferation”
Currently multiple clinical trials in the use of a
ketogenic
diet with various combinations of treatments
Slide67Dichloroacetate and cancer: new home for an orphan drug?
Biochim
Biophys
Acta
, 2014
Treatment for disorders of mitochondrial metabolism
Inhibits pyruvate DH kinases with reactivation of Pyruvate Dehydrogenase complex and oxidative phosphorylation
Redirects glucose metabolism from glycolysis to oxidation—reversal of Warburg effect
Preclinical and small clinical trials suggest additive/synergistic anti-proliferative and pro-apoptotic effects in combination with standard agents
Slide683-Bromopyruvate a fast acting, promising, powerful, specific, and effective “small molecule” anti-cancer agent taken from labside to bedside
J
Bioerg
Biomembr
, 2012
Cancer cells exhibiting the Warburg effect have markedly increased levels of the enzyme Hexokinase-2—key enzyme in metabolizing glucose to lactic acid
Discovery of 3-BP as powerful blocker of HK2 (and possibly other mechanisms)
Study of 19 rodents with advanced cancers treated with 3-BP showed eradication of cancers in 100% of test animals
Case study of teenage boy with terminal liver cancer (95% of liver replaced by cancer) showed clearing of liver cancer by direct injection of 3-BP into hepatic artery
Slide69A brief critical overview of the biological effects of methyglyoxal and further evaluation of a methylglyoxal-based anticancer formulation in treating cancer patients
DrugMetabDrugInteract
, 2008
Methylglyoxal a product of normal cellular metabolism
Found naturally in New Zealand
manuka
honey—likely active ingredient responsible for antibacterial effects
Inhibitor of Glyceraldehyde-3-phosphate Dehydrogenase and Mitochondrial Complex 1 in cancer cells
Some in-vitro studies showing possible AGE’s toxicity
In vivo studies not showing any toxicity
Slide70Methylglyoxal (cont)
Three phase human study of cancer patients showed benefit to most patients including many complete remissions
Symptomatic improvement in patients with progressive disease (palliative)
Free of toxic effects
Slide71Melatonin suppression of aerobic glycolysis (Warburg effect), survival signaling and metastasis in human leiomyosarcoma
J Pineal Res 2016
‘These results demonstrate that nocturnal melatonin directly inhibited
tumour
growth and invasion in human LMS via suppression of the Warburg effect, LA uptake and other related signaling mechanisms.’
Slide72The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials
Cancer
Chemother
Pharmacol
, 2012
Meta-analysis of 8 RCTs of solid tumor cancers
Melatonin as adjunct treatment with chemotherapy or radiotherapy
Approximately doubled complete and partial remission rates and 1 year survival rates
Dramatically decreased
radiochemotherapy
-related side effects including thrombocytopenia, neurotoxicity, fatigue
Slide73Metabolic cancer treatment: Intermediate results of a clinical study
Cancer Therapy, 2014
Based on preliminary study of 27 compounds known to affect glucose metabolism
Reduced to 7 most effective compounds-- then used in pairs to determine most effective combination
Clinical trial done on 40 patients with terminal cancers—life expectancy of 2-6 months using a combination of
alphalipoic
acid and
hydroxycitrate
along with addition of low dose naltrexone
Slide74Metabolic cancer (cont.)
Patients treated with either metabolic therapy alone or in combination with chemotherapy or hormonotherapy
Results after 1 year: 68% of metabolic therapy only group surviving
70% of combination therapy group surviving
Side effects of metabolic therapy are minimal
Slide75Promising new metabolic treatments
Gallium
maltolate
—interfering with cancer iron metabolism (and likely other metabolic functions)
Phloridzin
—from apple skins and roots. Blocking glucose transporters (GLUT receptors), interfering with cancer cells ability to bring glucose into the cells.
Salicinium
—sugar complex molecule, interfering with glycolysis and possibly improving susceptibility to immune system surveillance.
Slide76The hallmarks of cancer
Cell 2000
Self-sufficiency in growth signals
Insensitivity to growth inhibitory signals
Evasion of apoptosis
Limitless replicative potential (immortal)
Angiogenesis
Tissue invasion and metastasis
? All hallmarks can result from mitochondrial damage and loss of required energy supplies
Slide77Genetic Damage and Instability
Natural compounds that protect DNA from damage and mutations:
Hundreds or thousands of compounds in nature—antioxidant vitamins (
eg
.
Vit
C,
VitE
) and minerals (
eg
selenium,zinc
),
bioflavenoids
(
eg
.
Curcumin
, EGCG,
Resveratrol
),
detoxificants
(
eg
. Alpha-
lipoic
acid, NAC )
Slide78Abnormal Expression of Genes
Oncogenes
(encourage cell proliferation and growth) and cancer suppressor genes (decrease growth, increase differentiation/maturation, promote apoptosis-normal cell death)
Natural compounds that can help to normalize gene expression--turning off and on of appropriate genes:
Vit
C,
Vit
E, Melatonin,
Vit
D,
Curcumin
, EGCG,
Genistein
,
Resveratrol
, Selenium,
Quercetin
Slide79Signal Transduction
‘Messenger chemicals’ giving signals to cells that regulate growth.
Natural compounds helping to normalize inappropriate signals:
Boswellia
,
Curcumin
, EPA &DHA, Various
flavenoids
, Garlic, Melatonin,
Parthenolide,Resveratrol
,
Vit
E
Slide80Cell-to-cell Communication
Cancer cells can act ‘independently’ from neighboring cells and the body as a whole, ‘ignore’ feedback/communication from the ‘cooperative’ cells of the healthy body
Natural compounds that can enhance communication:
Vit
A,
Genistein
, EGCG, Melatonin,
Resveratrol
, Selenium,
Vit
D
Slide81Invasion and Metastasis
One of the defining characteristics of cancer.
Utilizing enzymes to facilitate.
Natural compounds that reduce activity of various involved enzymes (
eg
.
Collagenases
,
hyaluronidase
,
heparinase
):
Boswellia
,
Centella
asiatica
(
gotu
kola),
Proanthocyanidins
,
Resveratrol
,
Vit
C,
Vit
A,
Curcumin
, EGCG, EPA
Inhibiting cell migration:
Vit
D, EPA/DHA,
Genistein
, Melatonin, Ginseng
Slide82Immune Surveillance
Natural compounds enhancing immune system function or decreasing immune evasion: various mushrooms (
eg
shiitake,
maitake
, etc), Zinc, Selenium, Glutathione,
Vit
C, Melatonin, Enzymes (
eg
bromelain
, pancreatic)
Slide83Blood Sugar and Insulin Regulation
Tumors consume glucose at a rate of 10-50 times higher than normal tissue
Diabetics more prone to cancer of breast, prostate, colon, liver, and pancreas.
Insulin (and IGF-1) stimulate growth of many cancers.
Approaches to help reduce blood sugar and insulin levels: low refined carbohydrate diet,
vit
D,
Berberine
, Cinnamon, Chromium,
Coffeeberry
extract, Holy basil
Slide84Example Nutritional Support Treatment Plan
Vit
D 5000
iu
Vit
A 10,000-20,000
iu
Vit
K2 45 mg
Vit
E (
tocotrienols
)
Multi-mineral (especially including good levels of Magnesium, Zinc, Selenium)
Omega-3 (fish oil) 2000 mg (EPA+DHA)
Curcumin
(enhanced absorption) 500-800 mg
tid
Green tea (EGCG 300-350 mg
tid
)
Resveratrol
250-300 mg,
Berberine
500 mg bid
Foods: Nuts and seeds (minerals
incl
selenium),
Brocolli
sprouts (
sulforaphane
), Seaweed, Mushrooms
Ketogenic
diet +/_ ketones
Slide85Possible elements of a Metabolic Treatment
Ketogenic diet +/- hyperbaric oxygen
Alpha-lipoic acid—high dose oral and/or intravenous
Hydroxy
-citrate
DCA
3-BP
Phenyl-butyrate (Glutamine metabolism)
Methylglyoxal
Melatonin
Creatine
Ketone supplement
Slide86Therapeutic Goals
Modify/correct as many cancer promoting factors as possible.
Impair underlying cancer metabolism
The more mechanisms that can be influenced simultaneously, the better the expected effect.
Utilize synergism (“teams”)—increased effectiveness at lower doses with combinations of compounds with related activity.
Minimize toxicity to healthy cells from
cytotoxic
treatments.