Edge-CAM Regimen 4.0
24 June, 2013
Curcuminoids + D3 + EGCG + Melatonin + Selenium +
[new] Isoflavones + RYR + OFA [see below]
CoQ10-RNP (riboflavin (Vitamin B2) + niacin + pyridoxine (B6))
Boswellic Acids/AKBA + DHA + Parthenolide + Resveratrol*
Elevated risk BC
*Re resveratrol, see caution below.
Newest updates [24 June 2013]:
Consumption of ≥10 mg (soy-derived) isoflavones/daily was associated with significant reduced risk of recurrence [Nechutta, Am J Clin Nutr 2012].
Sources: unsweetened soymilk (e.g., Westsoy)= 30 mg isoflavone per glass.
Dosing: 60+ mg daily (2 glasses soymilk or equivalent). Current weight of the evidence supports safety of soy in breast cancer populations.
Statins and HD-RYR (High-dose Red Yeast Rice)
Statin use is associated with decreased breast cancer mortality in women with localized or metastatic tumors [Murtola, ASCO 2013].
Source: Nature's Plus Herbal Actives Red Yeast Rice Extended Release -- 600 mg - 120 Mini Tablets.
Dosing: Using red yeast rice (RYR) as pharmaceutical statin equivalent, high-dose consumption = 2400 mg RYR extract (4 tablets daily).
Important: Like any statin, RYR depletes CoQ10, so supplement with at least 100 - 200 mg of CoQ10.
HD-OFA (High-dose Omega-3 Fatty Acids)
High-dose omega-3 fatty acids supplementation favorably modulates breast tissue biomarkers including proliferation [Fabian, ASCO 2013].
Source: Barlean’s Fresh Catch Signature Fish Oil is the most concentrated source (2 to 2.5 teaspoons daily).
Dosing: At least 4 g daily of omega-3-acid with EPA.
- Primarily for endocrine disease, and especially during tamoxifen therapy.
- Potential benefit in other forms of breast cancer requires further data.
- No standardization issue
- Dose: 90 - 100 mg CoQ10 + riboflavin (Vitamin B2) 10 mg + niacin (30 mg) + 100 mg pyridoxine (B6)
- The just published Multiethnic Cohort from Galina Lurie and colleagues has found that higher circulating levels of vitamin B6 are associated with a reduced risk of invasive breast cancer in postmenopausal women with hormone receptor-positive tumors, with a 30% reduced risk of invasive breast cancer compared with women with lower B6 levels.
- [A Caution re CoQ10: bear in mind that although there may be some methodological questions still unresolved, still one Multi Ethnic Cohort (MRC) study (2010) found that higher CoQ10 levels in postmenopausal women may be associated with increased breast cancer risk, exerting a potentially negative role in the development, and progression, of BC. And although the later SWHS study (2011) found an inverse relationship between circulating CoQ10 and breast cancer risk, nonetheless those authors candidly and commendably acknowledge that there may be no contradiction and that the findings of the large MEC prospective trial cannot be ignored other than at peril, since it is plausible that there a may be a possible nonlinear (U-shaped) association of CoQ10 with risk, with elevated risk both at the very low and at the high ends. I would therefore caution not exceeding a median levels of 90 – 120mg/daily of CoQ10 supplementation]
- Note: Vitamin B2 and niacin (B3) are often found in these amounts in multivitamins, and so supplementation may not be necessary.
- Optimal Formulation: Standardized to deliver at least 90%+ curcuminoids (the antitumor component) content, and Sabinsa-certified (the pharmaceutical grade formulation used in the studies). One leading pharmaceutical grade product comes from the Doctor's Best brand, as the product Best Curcumin.
- Optimal Dosing: Minimal effective dosing is 500mg / daily of curcuminoid component (one capsule daily), but this can be escalated to up to at least 1500 to 2000 mg / daily in: (1) advanced disease and metastatic settings, or in, (2) elevated risk contexts. A new study from Mathilde Bayet-Robert at the Centre Jean Perrin has established although the MTD (maximum tolerated dose) of curcumin is 8000 mg/daily, the recommended dosing for near-optimal clinical benefit in human trial of women with advanced or metastatic breast cancer is 6000 mg/daily.
- Take curcumin towards to end of a large meal, preferably in three divided doses. When using a piperine (Bioperine) bioavailability-enhanced curcumin formulation, be aware that the piperine ingredient may enhance (but fortunately not decrease) the efficacy of other agents consumed approximately concurrently, so if at all possible, separate co-consumption by at least one hour.
- I consider: (1) TNBC, (2) IBC, (3) MBC, and (4) HER2+ disease as contexts of elevated risks, in which cases optimize at 6000 mg/d.
- Evidence suggests that piperine itself has antitumor activity of its own.
- New evidence reported (9/09) from researchers at the Winship Cancer Institute and Emory University suggests that curcumin may be genotoxic (DNA-damaging), of particular benefit to triple negative and BRCA1 deficient patients, the first ever demonstration of the specific TNBC-potential activity of curcumin, showing curcumin-induced promotion of apoptosis and prevention of growth and migration of TNBC cells.
EGCG/Green Tea Extract
- Recent data has shown that EGCG functions as an DNMT inhibitor, a function it shares with parthenolide, and is synergized by co-administration with an HDAC inhibitor such as parthenolide and/or curcumin, constituting the backbone of what's called epigenetic reprogramming (which may facilitate the conversion of breast cancer subtypes to more prognostically favorable, less aggressive ones).
- EGCG potentiates the efficacy of radiotherapy in breast cancer patients, while showing strong anticancer activity (per the human clinical trial of Zhang et al., Curr Mol Med, 2012), and has been found of benefit in all BC subtypes including TNBC, and works synergistically with traditional oncotherapy agents (Suganuma et al., Cancer Sci, 2011; Li et al., Nutrceut Cancer, 2012).
- Activity is synergistic with curcumin.
- Optimal Formulation: standardized to > 97% polyphenols, with approx 45% or higher of the active ECGC component, as in NSI Green Tea Extract.
- Optimal Dosing: 250 - 500mg / daily, so 2 capsules daily, taken with meals, would be required (delivering 450mg/daily EGCG content. If sensitive to the modest caffeine content full daily dose should be completed before 5PM, or use an alternative caffeine-free formulation.
- Optimal Formulation: No standardization issue with melatonin. Natrol Melatonin delivers 5 mg per capsule.
- Optimal Dosing:20mg / daily (45 - 60 minutes before sleeptime). Begin with 5mg / daily, and step up an additional 5mg every 3 to 4 days to the 20mg level; note however that any amount at or above 3mg/daily, although not optimal, may still be beneficial and preferable to no melatonin consumption).
- New research from the Institute of Biological Medicine in Milan) has found that melatonin added to to AI therapy in metastatic BC patients with poor clinical outcome (metastases to lung, liver, or bone) achieves an impressively high objective tumor response (complete responses (CR) 14% + partial responses (PR) 43%) of 57%, compared to the norm for AI monotherapy reported in the literature which is generally below 40%, with an additional 29% stable disease (SD), yielding a disease control rate (DCR: CR + PR + SD) of 86% in a poor outcome metastatic disease population, suggesting the enhancement of AI therapy via melatonin.
- Optimal Formulation: Vitamin D3 (which is the cholecalciferol form), not Vitamin D2 (which is the ergocalciferol form). No standardization issues.
- Optimal Dosing: The best way to determine the optimal level for antitumor benefit is through a simple 25(OH)D (Vitamin D3) assay or laboratory test, also known as a cholecalciferol assay / test (or the "25-Hydroxy Vitamin D" test). Aim for a target level for 25(OH)D of at least 66 ng/ml which typically will require at least 3000 - 4000 IU of Vitamin D/daily, remembering that each 1000 IUs of Vitamin D elevates serum 25(OH)D levels approximately 10 ng/ml above base.
- Benefits of High-Optimal 25(OH)D Levels
It is known that 52 ng/ml levels are associated with a 50% reduction in risk of breast cancer, compared to 13 ng/ml (per Cedric Garlands's 2006 APHA review). And there is now compelling human clinical data in a case study presented by John Sievenpiper and Simon Pearce with the Royal Victoria Infirmary of high-dose Vitamin D3 (HD-D3) averaging at 10,000 IU/daily that has induced complete remission of distant metastasis (bone), with implications beyond bone metastases.
- Therefore, for (1) patients with active malignancies, and/or (2) those at elevated risk of malignancy, recurrence or metastasis, a target level of at least 66 ng/ml would be of greater potential benefit.
- The Special Needs of African-American Women:
In addition, adequate testing and supplementation are even more imperative for postmenopausal African-American women who, as the NHANES III study has demonstrated, have lower serum 25(OH)D concentrations at all ages than do whites, and the research of John Aloia at Winthrop University Hospital has established that this population is relatively resistant to low-dose supplementation, finding that supplementation with 800 - 1000 IU vitamin D per day for 3 years effected absolutely no raising of 25(OH)D or PTH concentrations , in contrast to other racial/ethnic populations.
- But note that there is considerable interpersonal variation, so retesting is prudent: three consecutive monthly readings are advised to assure optimal 25(OH)D levels (amounts of 10,000 IUs/daily and even above have been found unproblematic).
- VHD-D3 for AI-Induced Disability
It's been recently established that Vitamin D deficiency and insufficiency may be a, if not the, major contributor to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs): Carol Fabian at the University of Kansas, along with Qamar Khan and their colleagues, showed that supplementation with VHD-D3 (very high dose Vitamin D3) in the form of injectable 50,000 IU weekly can reduce musculoskeletal symptoms and fatigue in women with suboptimal vitamin D levels. At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml). 25(OH)D levels >40 ng/ml were achieved in all women put on 12 weeks of 50,000 IU D3 supplementation with no adverse effects, and after 16 weeks of AI therapy (letrozole (Femara)), more women with median 25(OH)D levels >66 ng/ml reported no disability from joint pain than did women with any levels below, by an order of 52% versus 19%, respectively. Thus, very high levels of 25(OH)D, >= 66 ng/ml, are needed to significantly reduce disability and fatigue from AI-induced arthralgias/myalgias and associated fatigue.
In addition, Aruna Krishnan and David Feldman's team at Stanford have just reported that the combination of calcitriol, the active form of vitamin D3, and an AI yields: (1) AI augmentation by acting as a SAM, selective aromatase modulator, increasing aromatase expression in bone - but decreasing it elsewhere - helping to reduce the estrogen deprivation induced AI side effects on bone; (2) suppression of both estrogen synthesis and biological activity in a tissue-selective manner, causing enhanced cancer cell inhibition in both BC cells and in the surrounding breast adipose tissue; and (3) an indirect anti-aromatase effect due to COX-2 suppression. Thus the powerful anti-aromatase activity of Vitamin D3 can enhance the anti-proliferative effect of AI therapy, while ameliorating the AI-induced adverse effects on the bone.
- Vitamin D3 for TNBC: New evidence suggests that the triple-negative breast cancer (TNBC) phenotype has the lowest average vitamin D level and the highest percentage of patients that are vitamin D deficient, strongly suggesting that low vitamin D levels are characteristic of the triple-negative phenotype. In a case series presented by Christa Rainvillle and colleagues, patients with the more aggressive triple-negative phenotype had a mean serum vitamin D level of 20 ng/ml compared to a mean of 36 ng/ml for normal volunteers. This may help to account for the fact African American women have the highest breast cancer specific mortality rates, the lowest serum levels of 25(OH)D, and the highest incidence of aggressive triple-negative or basal-like tumors (39%), as Lisa Carey and colleagues found in their Carolina Breast Cancer Study of race, breast cancer subtypes, and survival, and the Rainville findings further support that lack of vitamin D transport into cells may contribute to aggressive phenotypic expression (especially of TNBC, but possibly also, evidence suggests, of aggressive HER2+ and IBC disease). Therefore, my strong guidance for TNBC patients is to assure consistent (3 consecutive monthly readings) optimal (66+ ng/ml) Vitamin D3 levels, with periodic retesting (every 6 months).
- Clinical Lessons re High Dose Vitamin D3:
Target 25OHD (aka, 25(OH)D Vitamin D3 Level
Optimal Bone Health
> 42 ng/ml
> 52 ng/ml
> 66 ng/ml
> 66 ng/ml
Boswellic Acids [For special populations]
- Boswellic acids, derived from Boswellia serrata (Frankincense), are powerful LOX inhibitors, where the LOX-5 pathway has been implicated in the inflammatory component of many cancers including breast cancer, and especially of brain cancer or brain metastasis.
- Optimal Formulation: (1) Source Naturals Boswellia Extract, delivering 262 mg of boswellic acids per tablet, and (2) NSI Boswellia Extract, delivering 200 mg of boswellic acids per tablet.
- Optimal Dosing: Certain breast cancer classes have an elevated risk for development of metastases to the brain (CNS metastasis), and this includes (1) TNBC (and probably basal and BRCA1 mutated) and (2) HER2+ disease, and therefore it may be of prophylactic benefit for these populations to supplement with boswellic acids. Except for active brain carcinoma or metastases, dosing should deliver no less than approximately 500 - 600 mg boswellic acid daily.
- Note on Optimal Dosing / Scheduling and Components:
Many clinical trials have used the Sabinsa Boswellin product (under different labels), which yields approx. 150 to 162mg per dose, with the schedule typically being 3X to 4X daily, for a daily dosing of 450 - 486mg of boswellic acid content (not the extract itself) at the 3X schedule, and 600mg - 648mg daily at the 4X schedule. Therefore, following a Sabinsa-based schedule, the range would be from a low of 450mg daily to a high of 648mg daily, the general rough rule being to consume no less than 500 - 600mg daily as an average.
- So for example the Nature's Herb Boswellin delivers 150mg standardized boswellic acids per tablet, while Now Foods Boswellin delivers 162mg per capsule. The Source Naturals Boswellia Extract product is one of the higher potency formulations, delivering 262mg per tablet. And note that some European studies are using up to 1000mg of boswellia extract for active disease, which would typically deliver 650 mg (at 65%) to 950mg daily of boswellic acid content.
- There is a second approach emerging to boswellia standardization: some studies are standardizing on the AKBA component of boswellic acids, known from recent research to be the critical apoptotic, anti-angiogenic and anti-proliferative component, with dosing in the range of 45 - 100mg AKBA content daily. The NSI 5-Loxin product is one such AKBA-standardized product, delivering 22.5mg per capsule, hence dosing would between 2 and 4 capsules daily (45mg to 90mg, respectively).
- The AKBA approach, as opposed to the overall boswellic acids (BA) approach, is more targeted, seeking to assure that of all the many boswellic acids, the critical AKBA boswellic acid component is delivered precisely, so although we don't have data to resolve the efficacy comparison of the AKBA and BA approaches, the AKBA approach appears to be of higher assured quality delivery of antitumor activity.
- Important Note on Concurrent Food Intake:
Pharmacokinetic studies have revealed poor bioavailability for the most critical component of boswellic acids, AKBA, which may compromise efficacy. Therefore optimal administration is dosing with a high-fat meal which dramatically maximizes bioavailability and hence delivered efficacy; the high fat can be intrinsic to the meal, or realized just by adding at least 1 - 2 tablespoons or higher of olive oil.
Resveratrol [For special populations]
- Even though, as I noted, the potential benefit of resveratrol are not quite as mature as those on curcuminoids, EGCG and melatonin, I consider supplementation sufficiently motivated in these cases: TNBC, IBC, MBC, or HER2+, observing the caution below.
- Optimal Formulation: One of these pharmaceutical grade formulations:
(1) Now Foods Natural Resveratrol Mega Potency
(2) Enzymatic Therapy Resveratrol Forte
(3) NSI Resveratrol Grape Seed & Red Wine Extract
- [new] Optimal Dosing: Until now, the best extrapolation of the optimal anticancer dose of resveratrol has been approximately 100 mg resveratrol content / daily. But new evidence just published from Edwina Scott and colleagues at the University of Leicester based on several human clinical pilot studies now clarify that optimal anticancer therapeutic activity in humans requires 1 gram (1000 mg) daily. In contrast, the intake of resveratrol from red wine after moderate consumption, which is 250 mL (one medium glass) in a 70 kg (154 lbs) person would be 1.25mg/day, which is just 1/800th of the optimal dose (remembering of course that the overwhelming weight of the evidence shows that no amount of alcohol is safe, so only supplementation is viable).
An in press preclinical study of resveratrol from Masuyuki Fukui and colleagues at the University of Kansas found that that resveratrol strongly diminished the susceptibility of certain breast cancer cells, including triple negative (MDA-MB-231 cells)" to paclitaxel-induced cell death in culture, and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied).
Reishi (Ganoderma lucidum) Mushroom Extract [for IBC only]
- Michaela Hoffmeyer at the University of Texas and colleagues recently tested the hypothesis that the immunomodulatory, anti-inflammatory, and anti-cancer effects of the traditional Chinese medicinal (TCM) agent Reishi (Ganoderma lucidum) mushroom extract, may be effective against IBC progression and invasion, given accumulating evidence of its ability to inhibit proliferation, adhesion, migration, and invasion of cancer cells via the triterpenes component which exhibits cytotoxicity against cancer cells at high concentrations, and component polysaccharides that are immunostimulatory. The Reishi extract effectively inhibited proliferation of the IBC cell line, reducing cell-cell attachments and decreasing invasion of IBC cells. Reishi also down-regulated 52% of tumorigenesis genes in the IBC cells treated, and furthermore inhibited the MMP-2 and MMP-9 levels; this suggests that Reishi inhibits IBC progression via cell proliferation reduction, prevention of tumor emboli formation, and inhibition of invasion by reduced matrix MMP levels. So Reishi extract appears to be a natural agent with potential inhibition of IBC progression. (See IBC Watch).
- Optimal Formulation:
NSI Reishi Mushroom Extract is one optimally standardized (10% polysaccharides) product, delivering 50mg of standardized component per capsules.
- Optimal Dosing:
The goal would be 100mg active component daily, so dose at two capsules daily, preferably on an empty or near-empty stomach.
- Parthenolide, a strongly anti-inflammatory agent, is the primary biologically active agent in Feverfew commonly used for migraine and arthritis, and the focus of considerable investigation as a natural oncotherapeutic and cytotoxic agent in several malignancies including breast cancer.
- In endocrine/hormonal disease, Rebecca Riggins and colleagues at Georgetown demonstrated that parthenolide restored fulvestrant (Faslodex)-mediated suppression of cell growth, yielding 4-fold synergistic cell growth reduction and apoptosis enhancement (and this may not be restricted just to fulvestrant, but to other endocrine agents).
- In hormone-negative disease, including and especially TNBC, my own research in epigenetic reprogramming has uncovered parthenolide to be a natural HDAC inhibitor as well as a DNMT inhibitor, properties similar the investigational epigenetic agent vorinostat (Zolinza), so it too may like vorinostat have potential to change or modulate a challenging breast cancer subtype, TNBC, into a prognostically more favorable phenotype.
- Finally, Yang Liu and colleagues in Peking University demonstrated the activity of parthenolide against cancer stem cells, an activity that curcumin also shares.
- Dosing and Optimal Formulation
The inclusion of parthenolide into the Edge-CAM regimen is marked provisional solely because we as yet lack decisive dose-finding studies, but extrapolating from the existing preclinical and in vivo data, the target dosing would be hazarded on that basis to be approximately 6 mg of parthenolide content daily. Source Naturals Feverfew Extract delivers 200 mg of feverfew extract per tablet, standardized at 0.5% parthenolide content, so that yields 1mg/tablet, with optimal schedule being two capsules 3X daily with meals, supplemented with at least 81 (baby) to 325mg (adult) aspirin daily as coadministration with salicylates enhances activity.
- HD-Parthenolide: High-dose parthenolide in special circumstances - higher anti-inflammatory potency for example in the treatment of peritumoral (cerebral) edema in CNS disease to reduce reliance on steroid medication - is feasible and safe: studies have shown that parthenolide is essentially non-toxic, so dosing at levels of 2X to 3X the target 6mg/daily are plausible to determine if greater relief and benefit are attainable. A high-potency formulation is typically needed. One of the most concentrated in Solaray Migra Gard standardized at 0.7% parthenolide content in 350mg Feverfew capsules, yielding 2.45mg of parthenolide per capsule (in contrast to the Source Naturals product delivering 1mg per tablet).
DHA (Docosahexaenoic Acid)
- DHA is a lipid of marine origin, and is one of the two principal components of omega-3 fatty acids (OFAs), with preliminary studies showing both chemosensitization and radiosensitization activities, the enhancement of sensitivity appearing to apply preferentially to aggressive tumor cells.
- Phillippe Bougnoux and colleagues reported results of a phase II clinical trial in which DHA was added during a 7 - 10 day loading period before anthracycline-based chemotherapy (FEC) and then continued for the 5 months of chemotherapy, in a population of metastatic BC patients with compromised prognosis (68% had liver metastases in addition to other metastatic sites) with rapidly progressing visceral metastases (17 liver, 9 lung patients), along with 15 patients with bone metastasis, 5 with skin metastasis, and one with brain metastasis. The ORR (overall response rate) was 44% with one complete response (CR) and 10 partial responses (PR), and given that there were 11 stable disease SD cases, the clinical benefit rate (CBR) was 88%, with median overall survival (OS) significantly greater in the sub-population of patients with the highest plasma DHA.
- This clinical trial therefore confirms previous positive findings, and demonstrates that DHA + chemotherapy may improve the outcome of metastatic BC patients, with DHA chemosensitizing tumors.
- Vincent Blankaert and colleagues at IUT de Laval have found that DHA (docosahexaenoic acid) slows the proliferation of triple negative breast cancer cells (MDA-MB-231) and minimizes their metastatic potential, via decreasing proliferation, increasing apoptosis, and reducing the invasive potential of triple negative tumor cells.
- Dose: at 1.8 grams/d. Consult Consumerlab.com for high-quality approved products.
- Important: It was thought until recently that Vitamin E might abolish the DHA-induced sensitization (chemo- and radio-) of tumor cells, but Ailan Xiong and colleagues at the University of Texas have recently (2012) shown that positive anticancer activity of DHA-induced apoptosis in TNBC cells is only inhibited by the alpha tocopherol, while the gamma tocopherol form actually cooperates with and enhances the beneficial effect of DHA-induced apoptosis in TNBC cells. Therefore, TNBC users of DHA can gain even more anti-TNBC activity by supplementing with both DHA and the gamma (not alpha) tocopherol form of Vitamin E, and the alpha from should be avoided in TNBC patients.
Selenium has been found to induce p53 redox modification which has the potential for at least partial restoration of p53 function to mutant p53. This is important for TNBC tumors because the vast majority of TNBCs express a mutant p53, and such failure of p53 signaling is associated with chemoresistance of tumors to therapy, especially to DNA-damaging oncotherapy (see below).
- Therefore therapies directed toward restoring p53 function / signaling to the highly accumulated mutant p53 seen in most TNBC tumors can yield substantial benefit by improving the outcome of these oncotherapy for TNBC tumors in which p53 is prevalently mutated.
- A Tulane University study reported at SABCS 2009 demonstrated that selenium greatly increase the growth-inhibitory potency of genotoxic (DNA-damaging) chemotherapy (doxorubicin) in TNBC cell lines expressing mutant p53 and this represents a safe and highly effective approach for increasing the efficacy of genotoxic oncotherapies in the treatment of TNBC.
- The form of selenium used in the study (methylseleninic acid, aka MSA) is not readily commercially available, a non-inferor form is L-Se-methylselenocysteine (MeMSC) [best source Swanson Vitamins]; dosing is optimized at 200 mcg (micrograms) daily - single capsule - taken with a meal.
Anyone with TNBC who is on or anticipating genotoxic (DNA-damaging) oncotherapy, such as:
- platinum agents (cisplatin or carboplatin)
- cyclophosphamide (Cytoxan) (as in AC, TAC and CMF regimens)
- radiation therapy
- PARP inhibitor therapy
may benefit from such selenium complex supplementation.
A Brief Note on CAM Synergies:
Inclusion of an agent in the Edge-CAM regimen follows ten broad inclusion/eligibility requirements (and many exacting methodological and strength-of-evidence sub-requirements). Briefly, the components of the Edge-CAM regimen are (1) selected through a process of evidence-based review and critical appraisal (2) to exhibit multiple cross-confirmatory data of (3) efficacy, (4) safety and (5) absence of clinically significant adverse pharmacokinetic interactions as to their anticancer activity in both (6) chemopreventive and therapeutic contexts, and (7) at the in vivo level or higher (human clinical trials), and (8) must affect positively multiple molecular pathways (suggested and enumerated elsewhere) known to be active in carcinogenesis, tumorigenesis, malignant transformation and metastatic development and migration, and related malignant processes, and (9) with minimal potential for MDR (multi-drug resistance), or evidence of anti-MDR, activity, and finally (10) with non-interfering complimentary, additive or synergistic activity in concurrent administration with each other. Although therefore individual agent activity is required, the sum can manifest synergies of activity suggesting the core coherence of the regimen as a whole.
One example, of many: Rhonda Rosengren's team in New Zealand showed that the combination of EGCG + curcumin suppressed tumor growth in a mouse model of human breast carcinoma, finding the combination EGCG + curcumin to be synergistically cytotoxic toward MDA-MB-231 (triple negative) human breast cancer cells in vitro, while also decreasing ER+ tumor growth in vivo, and this correlated with a significant decrease in levels of VEGFR-1 (an angiogenic factor) in the tumors, and with tumor growth in the EGCG + curcumin group being inhibited by 49% compared to a tumor-suppressing rate of 31% in an EGCG only treated group.
Another example: curcumin is known to markedly sensitize tumor cells to the growth inhibition and apoptosis from the HDAC inhibitor vorinostat (Zolinza), suggesting synergy with the natural HDAC/DNMT inhibitor parthenolide and furthermore, given the ability of the HDAC inhibitor vorinostat to prevent the brain metastasis (micro and macro) of triple-negative breast cancer (Diane Palmieri et al.) via induction of DNA double-strand breaks, this suggests the potential of parthenolide +curcumin to inhibit brain metastatic colonization. We know that many tumors evade antitumor activities along one molecular pathway via activating one, typically several, other "escape" pathways (aka, cross-signaling), so that the degree of effective antitumor activity is dependent on multi-pathway targeting, and on any molecular pathways synergies that can be leveraged via concurrency. So in Edge-CAM, there are synergies, and broad-spectrum activities, everywhere. The whole is greater . . .
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