Nutraceuticals: Curative Integrative Cancer Treatment

Statement of Purpose: Although 75% of breast cancer patients may use integrative medicine, only 11.5% earlystage breast cancer patients believe integrative medicine has anticancer activity. The gap in users of and firm believers in integrative medicine indicates a need to increase awareness of integrative medicine’s applicability to curative cancer treatment. As diet, nutraceuticals, and traditional Chinese medicine are used by up to 82% of cancer patients who use integrative medicine, this paper focuses on nutraceuticals. As female cancer patients are most likely to use integrative medicine, nutraceuticals specific to breast, cervical, endometrial, and ovarian cancer are


Introduction
One-time integrative medicine use ranges from 42% in the United States to 75% in France [1].Upon cancer diagnosis patients are interested in conventional and integrative therapies [2].Post cancer diagnosis, 17% of Italian, 27% of Austrians, 35.9% of Europeans overall, 44% of German gynecologic cancer, 47.2% of Canadian, and 50% of German breast cancer patients use integrative medicine therapies [2][3][4][5][6].Consistent with this, integrative gynecologic cancer treatment is regarded as reasonable by 44.5%, and practiced by 24.2% of 310 Hessian region ObGyns who responded to a survey at an educational meeting [7].Nonetheless, extremes in integrative cancer treatment are evident.In one study, 75% of breast cancer patients used integrative medicine [8].However, as few as 11.5% of early stage breast cancer patients may perceive integrative medicine as having anticancer activity [9].Pediatric oncology integrative medicine ranges from 12% to 42% in Europe and 25% to 82% in the United States [1].
In Dutch pediatric oncology patients, female gender is predictive of integrative cancer use [10].Similarly, a cross-sectional study of three Pennsylvanian oncology centers found that being female (p=0.005),having breast cancer (p=0.016), and being at 12 to 36 months post diagnosis (p=0.017)most associated with integrative cancer treatment [11].Time from diagnosis had an n shaped association with integrative cancer treatment [11].Herbal and traditional Chinese medicine (TCM; excluding acupuncture) are received by 74.5% of patients at European integrative oncology centers [6].Among Italian cancer patients as few as 38.3% currently and as many as 84.2% previously used nutraceuticals comprised of diet, dietary supplements, and herbs [12].

Nutraceuticals
Nutraceuticals range from active constituent phytochemicals, minerals, and vitamins, through whole functional foods [13].Integrative nutraceutical therapies are based on biologic plausibility and have played an historical role in the development of the prescription pharmaceutical industry [14].Willow bark derived analgesic aspirin, Aspergillus terreus derived cholesterol-lowering lovastatin, Camellia sinensis (green tea) polyphenols derived sinecatechins for Condyloma acuminata (external genital wart [EGW]) treatment, Podophyllum species derived podophyllin for EGW and Molluscum contagiosum, as well as the chemotherapeutics taxol derived from Taxus brevifolia (Pacific yew tree), taxotere derived from Taxus baccata (European yew tree), topotecan derived from Camptotheca acuminata, and vincristine derived from Catharanthus roseus (Madagascar periwinkle), are just a few examples [15,16].Thus historically, nutraceuticals have been a starting point of new pharmaceutical drug development.
Nutraceuticals may provide benefits in conservative serving sizes: A cup of appropriately prepared green tea can provide 300 to 1,000 mg of epigallocatechin-3-gallate (EGCG) [17].Clinical trial EGCG dosing is based 10 mg/kg body weight, which can be achieved from green tea [18].Pharmaceuticals may require enormous amounts of the biologic source: 1,520 Taxus chinensis (Chinese yew) trees, an endangered species, are used to produce 1 kg of paclitaxel [19].Therefore, pharmaceuticals may require partially or totally synthetic manufacturing processes including plant cell suspension cultures to preclude extinction of their natural sources [19].
Most pharmaceuticals require a health care providers' prescription, whereas nutraceuticals, being food or dietary supplement products with health modifying effects do not require a prescription [20].Thus, nutraceuticals lie in a gray zone between prescription pharmaceuticals and open market household items [13].Nonetheless, nutraceutical agriculture and manufacturing may have to comply with good agricultural practices, good manufacturing practices, and standard operating procedures [21].Nutraceuticals undergo in vitro and in vivo pharmacokinetic, pharmacologic, therapeutic, safety, and head-tohead comparative effectiveness studies as do pharmaceuticals [20].Clinical pharmacology studies of nutraceuticals are essential for nutraceutical development and delineation [22].Nutraceuticals' use as prophylaxis against and treatment of pharmaceuticals' adverse effects is the subject of a separate paper, which also addresses nutraceuticals' inherent adverse effects.This paper reviews nutraceuticals as curative (alternative) cancer treatment, focusing on gynecologic cancer treatment.

Methods
PubMed searches in September 2016 and January 2017, and hand searches in August 2016, January 2017, and March 2017 were performed for English language, free full text articles published from 2012 onwards.Search terms were combinations of the key words: Homeopathy, phytochemicals, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, cancer, prevention, and treatment.Curative nutraceutical treatments were taken from these searches, as shown in Figure 1.Cytotoxic treatments and nutraceutical mechanisms of action were taken from these searches.These searches retrieved 184 articles, of which 127 articles were from the PubMed searches and 57 articles were from content driven hand searches.Of these, there were 14 duplicate articles, 16 redundant articles, and 55 extraneous articles, resulting in a total of 85 excluded and 99 included articles.

Nutraceuticals by phytochemical classification
This study does not review vitamins and minerals per se.However, whole fruits and vegetables, and fruit and vegetable derived phytochemicals may be vitamin and mineral rich.Fruit and vegetable derived phytochemicals may be studied based on mechanism of action, pathologies treated, or biochemical classification.By mechanism of action, the Matrix MetalloProtease (MMP) inhibitors aqueous cinnamon extract, green tea extract, curcumin, fenugreek derived steroidal saponin, and marine compound derived chitooligosacharides would be grouped together.However, each of these nutraceuticals has multiple mechanisms of action.Therefore, nutraceuticals and cancer treatment capabilities are initially presented based on chemical classification.There are numerous biochemical nutraceutical categories including alkaloids, lipids, organic acids and polysaccharides, organosulphurs, phenols, phytic acids, phytosterols, and terpenes, as indicated in Figure 2. Functional foods and other nutraceuticals comprised of constituent compounds will have constituent compounds from multiple biochemical classifications.The encompassing groups of alkaloids, organic acids, and polysaccharides will be briefly mentioned.Nutraceuticals from the secondary and tertiary groups will be briefly mentioned.Then attention will turn to those nutraceuticals pertinent to breast, cervical, and ovarian cancer treatment.

Alkaloids
Alkaloids are physiologically active, vegetable-based, organic, nitrogen-containing ring compounds.Alkaloids may belong to additional biochemical phytonutrient groups based on further chemical structure definition and resultant activity.Alkaloids can be co-constituents of a functional food, as is the case with Camellia sinensis tea leaves, which also contain flavonoids, steroids, gallic tannins and catecholic tannins (flavanols) [23].There are numerous alkaloid sub-classifications: Coffee derives aroma from trigonelline, a bitter alkaloid, and bitter taste from caffeine, a purine-like alkaloid [24].Alkaloids include colchicine from Colchicum autumnale (autumn crocus or meadow saffron), scopolamine/hyoscine from Hyoscyamus niger (henbane or stinking nightshade), physostigmine from Physostigma venenosum (Calabar bean), reserpine from Rauwolfia serpentine (Indian snakeroot or devil pepper), and taxol from Taxus brevifolia (Pacific yew) [24].

Organic acids and polysaccharides
Organic acids and polysaccharides are mentioned first as these are encompassing chemical composition groupings.Constituents thereof will belong to additional biochemical phytonutrient groups based on chemical structure and resultant activity.Organic acids are carbon containing acids.Polysaccharides are comprised of bonded sugar molecules.
Organic acids: Organic acids are inflammatory mediators with antioxidant, chemopreventive, and hepatoprotective properties [25].Cinnamic acid in Aloe vera, ellagic acid (a polyphenol organic acid, found in berries, green tea, guava, pecans, and walnuts), ferulic acid in oats and rice, gallic acid in tea, oxalic acid in coffee, spinach, and tea, and salicylic acid in peppermint are a few examples [25].Ellagic acid is a reactive epoxide scavenger that inhibits DNA methylation and DNA topoisomerase [26].

Polysaccharides:
Mushrooms are immune boosting chemopreventive polysaccharides [25].Fibrous polysaccharides also bind carcinogens, lower bile acids, and modulate estrogen metabolism [26].Polysaccharides from the TCM adaptogen ginseng up regulates granzyme and perforin expression and increases the whole blood natural killer cell (NKC) concentration leading to increased NKC cytotoxicity and decreased radiation therapy adverse effects [27].Perforin forms pores in target cells allowing serine protease granzyme to diffuse into target cells and initiate apoptosis.

Organosulphur compounds
Sulphur's pungent odor is a hallmark of the organosulphur compounds comprised of indoles, thiosulfonates, and isothiocyanates.Organosulphur compounds, which include indole-3-carbinol (I3C) and diindolylmethane (DIM), are commonly derived from cruciferous vegetables.Cephalosporins which were developed from Acremonium fungi and penicillin from Penicillium fungi are also organosulphurs.
Indoles and Thiosulfonates: Indoles and thiosulfonates result from the ingestion and digestion of some cruciferous vegetables [25,28].
Therefore, it is biologically plausible and ecologically reasonable that isoprenoid-phospholipid conjugates be studied for potential medicinal purposes [32].

Phenols
Phenols which may be best known for the fruit and vegetable rainbow have a phenylalanine base.Coumarins, flavonoids, lignans, polyphenols, quinones, stilbenes, tannins, and xanthones, comprise the phenols category.gram of Camellia sinensis leaf extract contains 700 mg of phenols, of which 14 mg are flavonoids [23].
Tannins: Fruits' astringency may derive from tannins [47].Plant derived tannins are subdivided into hydrolysable tannins that are ellagic acid or gallic acid esters and condensed, non-hydrolysable tannins that are oligo-or polymeric proanthocyanidins [47].Brown algae derived tannins are a separate class, phlorotannins.Tannins may have 12 or more hydroxyl groups and five or more phyenyl groups.Gallic acid and flavan-3-ols may be classified as pseudo tannins.Condensed, non-hydrolysable tannins, which include flavan-3-ols are also classified as flavanols, in which category catechins were mentioned above.
Hydrolysable or pyrogallol-type tannins: Punicalagin, ellagic acid, punicalin are ellagitannins, while gallagic acid is a gallotannin.Carob pods have 0.95 mg/gm of hydrolysable tannins, while carob fruit have 0.237 mg/gm to 1.647 mg/gm of gallic acids, which is the third highest gallic acid content after chestnuts and cloves [47].Carob fruit fiber contains at least three sets of gallic acid based tannins: Epigallocatechin with four gallic acid units, hexose with two to five gallic acid units, and pentoses with two gallic acid units [47].Carob fruit fiber also contains prodelphinidin dimer and trimer [47].
Terpenes: Terpenes are single or multiple hydrocarbon compounds, categorized as saponins, and mono-or higher terpenoids, including tetraterpenes, based on the number of carbon atoms and isoprene residues [25].

Whole Plant Nutraceuticals Cardamon
In female Swiss albino mice, cardamom, garlic, and saffron are chemoprotective against DMBA induced skin cancer [28].Cardamon stimulates phase II detoxification and anti-oxidation in female Swiss albino mice with DMBA treated skin and livers [28].Cardamom contains numerous phytochemicals, some of which are mentioned below.Phase I trials of limonene, a major constituent of cardamom suggest breast, colorectal, and prostate cancer inhibition with minimal toxicity at doses up to 100 mg/kg [28].D-Limonene is metabolized to perillyl alcohol, which inhibits G-protein isoprenylation [26].D-Limonene inhibits gastric and lung cancers and leukemia [28].1,8cineole inhibits and induces apoptosis in SK-MEL-28 human melanoma cells, B16-F1 murine melanoma cells, and Molt 4B and HL-60 human leukemia cells [28].Linalool uses p53 upregulation against leukemia, and inhibits renal adenocarcinoma and amelanotic melanoma [28].α-Pinene and α-Terpineol are anti-inflammatory to oral buccal cells [28].Myrcene is chemoprotective against DMPA in rats, and apoptotic in human hepatoma cell lines.Trans-nerolidol is cytotoxic to A-549 human lung carcinoma cells and DLD-1 cells [28].

Marine compounds
Ecteinascidia turbinata, the source of the active ingredient of Trabectedin, approved for the treatment of platinum-sensitive ovarian cancer and tumor soft tissue sarcoma, displays in vitro and in vivo transcription factor inhibition [79].Elysia rufescens derived Kahalalide F, is the basis for synthetic PM02734, which is in Phase II clinical trials for evaluation of H322 and A549 cell line apoptosis [79].Kahalalide F inhibited breast, liver, and pancreatic cancer, as well as melanoma in Phase I trials.Spisula polynyma derived ES-285-HC1 has inhibited solid hepatocellular, prostate, and renal cancer in vivo [79].Dicathais orbita containing the indole derivatives tyrindoleninone, tyrindolinone, 6-bromoisatin and 6,6′-dibromoindirubin, demonstrated in vivo apoptotic activity against azoxymethane exposed rat distal colon cells [79].Dicathais orbita derived tyrindoleninone and 6-bromoisatin are twice as apoptotic to the KGN tumor-derived granulosa cell line than to normal primary human granulosa cells (HGC), 66% to 31%, respectively [79].The biological plausibility of 6bromoisatin containing compounds will be presented in a separate article on oncologic homeopathic remedies.

Effect on Breast, Cervical, and Ovarian Cancers
As known nutraceutical inhibition of endometrial cancer focuses on I3C, this section focuses on breast, cervical, and ovarian cancers [26].
In vitro and in vivo mouse studies showed that the flavone, chloroform extracted luteolin from Eclipta alba (Bhringraj) dose and time dependently selectively activates intrinsic apoptosis by releasing mitochondrial apoptogenic proteins into the cytosol, inhibiting caspase-9, up regulating pro-apoptotic molecular chaperone heat shock protein 60 (Hsp60) and down regulating anti-apoptotic protein XIAP in MCF-7 and MDA-MB-231 cells, but spares MCF-10A normal breast epithelial cells [89].Luteolin was also found to be more active than the twice as available coumarin wedelolactone component of E. alba [89].Chloroform extracted E. alba luteolin was effective at 50, 100, and 200 μg/ml.Future studies should explore the efficacy of lower concentrations.

Ovarian Cancer
The 71 and 87 percentage point survival advantages between Stage 1 and Stages IIIC and IV ovarian cancer respectively indicates a need for more effective treatment modalities for advanced stage ovarian cancer and mechanisms for ovarian cancer prevention [62].However, a brief literature search suggests that much more could be done to find nutraceutical therapies targeted to ovarian cancer treatment.

Future Research
Research is needed to determine which of the whole plant or organism, the natural phytochemical component, the semi-synthetic phytochemical, or the completely synthetic phytochemical, is the most efficacious form of a nutraceutical.Crude extracts can derive anticancer activity from phytochemical components that are removed with additional processing.This is the case with Ferula extracts that lose phenolic components when purified to terpenoid coumarins [74].However, components of the whole plant or intact portions of the plant can have antagonistic effects, necessitating separation for maximal beneficial effect.For instance, quercitrin appears to antagonize M. pajang from which it is derived [72].Trials of I3C should evaluate the concentration of the I3C metabolite DIM present following administration and metabolism of I3C [28].Studies on cineole should determine the equivalence, if any, between 1,4-Cineole, the major phytochemical in cardamom, and 1,8-cineole, the most studied cineole [28].Similarly, clarity is needed as to the activity of each isomer of limonene.All studies on isomeric phytochemicals should specify the isomer used for clarity, efficacy, and adverse effect ascertainment.
Similarly, delivery modality effectiveness for nutraceuticals displays enormous variation.Improving oral nutraceutical bioavailability is an emerging discipline [97].While nano-encapsulated EGCG is 10-fold more efficacious than non-encapsulated EGCG, and berberine and curcumin act similarly, kaempferol is significantly less efficacious when encapsulated [43].Nutraceutical microbial fermentation can improve bioavailability and antioxidant efficacy [45].Therefore, the optimal delivery modality for each nutraceutical's optimal efficacy should be determined.In this light, quercetin is being studied as an enhancer for green tea polyphenol bioavailability and activity [98].Pro-drug derivatives may need to be developed [52].Similarly, with synthetic analogs, bioavailability enhancement may be possible without adverse effects as displayed by CYD-6-28 [69].Then, the focus can shift to making manufacturers supply pharmaceutical grade nutraceuticals in the most efficacious delivery modality.
In vivo trials of withaferin A for ovarian adenocarcinoma treatment are a logical progression from successful in vitro CaOV3 and SKOV3 cell line studies [96].Additional trials of M. pajang may indicate if a breast, cervix, or colon cancer treatment can be realistically pursued [72].The P. macrocarpa extracts can be further studied for breast and ovarian cancer [86].The main cytotoxic constituents of M. indica L. 's ethanolic kernel extract could be determined and studied in vivo [88].C. maculatum ethanolic extract should undergo in vivo murine trials against A375, A549, HeLa, HepG2, and WRL68 cell lines, to assess efficacy and tolerability.Tangeretin, nobiletin and 5-AcTMF should be further trialed for breast, colon, leukemia, myeloma, and NSCLC treatment [52][53][54].BITC should be further studied for breast cancer treatment [82].
Clinical trials of silibinin, Ganoderma lucidum polysaccharides and ganoderic acids, cordycepin from Cordyceps millitaris, EPA, γlinolenic acid, Yangzheng Xiaoji and DME25 may lead to antimetastatic drug candidates [77].Comparative effectiveness trials of EGCG, silibinin, curcumin, melatonin, oleanolic acid, resveratrol, withaferin A, enterolactone, kaempferol, and tripterine, listed from theoretically most anti-angiogenic activity to least anti-angiogenic activity, could determine which of these polyphenol nutraceuticals is the most anti-angiogenic for a given cancer [43].These nutraceuticals can also be trialed with conventional chemoradiation to determine if synergism will permit chemoradiation dose reduction.Nutraceutical treatment of TNBC is worthy of further investigation.β-Sitosterol, bitter gourd, caffeic acid phenethyl ester from propolis, chloroform extracted luteolin from Eclipta alba, Phaleria macrocarpa chloroform and hexane nobiletin extracts, Pseuduvaria monticola leaf menthol extracts (6E,10E) isopolycerasoidol and (6E,10E) isopolycerasoidol methyl ester, silibinin, and the tangeretin derivative 5-AcTMF may be potential drug candidates.Microenvironmental efficacy limitations of thymoquinone and its synthetic analogs should be performed to ascertain if microenvironmental effects limit thymoquinone's in vivo efficacy against bladder, bone, breast, lung, stomach, and pancreatic cancer cell lines, in addition to known limitations of thymoquinone in ID8-NGL mouse ovarian cancer [61,99].

Conclusion
Some nutraceuticals such as the Ferula species derived phytoestrogenic monoterpene umbelliprenin have very limited curative anti-cancer effects that can be limited to a single cancer.Other nutraceuticals, such as the natural MMP inhibitors, 3-azido WA, aqueous cinnamon extract, green tea extract, curcumin, fenugreek derived steroidal saponin, and marine compound derived chitooligosacharides should have a broader applicability.When the incidence and severity of a cancer, for example TNBC is considered, there is benefit in developing a nutraceutical that initially seems to be exclusively of single indication benefit.The breadth and depth of the nutraceutical clinical pharmacology literature suggests that an increased range of curative nutraceutical cancer treatments will become available.However, endometrial cancer treatment should be given as much consideration as have breast, cervical, and ovarian cancers.