Integrative Cancer Treatment - PowerPoint Presentation

Slide1

Integrative Cancer Treatment

Mel

Litman

MD

Weston Price Foundation, Baltimore

Nov 18, 2018

Slide2

Incidence 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

Slide3

Breast 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)

Slide4

Cancer 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

Slide5

PROGRESS 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

Slide6

The 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.”

Slide7

Serum 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.

Slide8

Dietary 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.

Slide9

Vitamin/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)

Slide10

EPIC-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.

Slide11

Long-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

Slide12

Multivitamins 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.

Slide13

Megadose 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.

Slide14

Vitamin 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.

Slide15

Lifestyle 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

Slide16

Antioxidants 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

Slide17

Shanghai 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

Slide18

San 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

Slide19

Neoadjuvant 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’.

Slide20

Women’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

Slide21

Women’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

Slide22

The 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

Slide23

ReprodBiolEndocrinol (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

Slide24

Fifteen-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)

Slide25

Treatment 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

Slide26

Chemotherapy 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%

Slide27

Chemoprevention 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

Slide28

Vit 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

Slide29

The 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

Slide30

Antioxidants/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

Slide31

Antioxidant 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

Slide32

Interaction 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.

Slide33

Rationale 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”

Slide34

Prasad, 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

Slide35

Antioxidants 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”

Slide36

Impact 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.

Slide37

Neuroprotective 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

Slide38

Neuroprotective 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.

Slide39

Antioxidants 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

Slide40

The 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

Slide41

Intravenously 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

Slide42

Intravenous 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

Slide43

Vitamin 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

Slide44

Ascorbate 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”

Slide45

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”

Slide46

Vitamin 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

Slide47

High-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.

Slide49

Guidelines 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.

Slide50

High-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 “

Slide51

Vitamin 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”

Slide52

Tumors: 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”

Slide53

The 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

Slide54

Mechanisms Targeted by Chemopreventive Agents

Slide55

Pro-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.

Slide56

Therapeutic 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’.

Slide57

End 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”

Slide58

On 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

Slide59

Cancer 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”

Slide60

Cytoplasmic 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)

Slide61

Cytoplasmic 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.

Slide62

Cytoplasmic mediation of malignancy

In Vitro Cell Dev Biol, 1988Nucleus from normal cell (no ‘cancer genes’) Transferred to cytoplasm of cancer cell Cancer cell

Slide63

Retrograde 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.

Slide64

Cancer 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

Slide65

Is 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”

Slide66

Carbohydrate 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

Slide67

Dichloroacetate 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

Slide68

3-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

Slide69

A 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

Slide70

Methylglyoxal (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

Slide71

Melatonin 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.’

Slide72

The 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

Slide73

Metabolic 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

Slide74

Metabolic 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

Slide75

Promising 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.

Slide76

The 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

Slide77

Genetic 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 )

Slide78

Abnormal 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

Slide79

Signal 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

Slide80

Cell-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

Slide81

Invasion 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

Slide82

Immune 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)

Slide83

Blood 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

Slide84

Example 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

Slide85

Possible 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

Slide86

Therapeutic 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.