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Nutraceuticals: Chemoradiation Sensitizers and Adverse Effect Resolvers

Background: Conventional cancer treatment is associated with resistant cancer development, treatment and quality of life limiting adverse effects, and patients’ inability to complete intended treatment plans. Conventional cancer treatment’s adverse effects lead 36.1% of cancer patients to seek integrative cancer treatments, which can provide a 15 percentage-point improvement in their health status. Therefore, a review of the extent of nutraceuticals applicable to conventional chemoradiation sensitization and adverse effect amelioration, as well as, for chemoprevention is valuable. Methods: PubMed searches in September 2016 and January 2017, and hand searches in August 2016 and January 2017 were performed for English language, free full text articles published from 2012 onwards. Search terms were combinations of the key words: Homeopathy, nutraceuticals, phytochemicals, cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, prevention, and treatment. Adjuvant characteristics, adverse effects, and chemoradiation sensitization treatments were taken from these searches. Findings: Organosulphurs are immunologic chemosensitizers. Terpenes can inhibit or reverse drug resistance. Epigallocatechin modulates estrogen receptor expression. Polyunsaturated fatty acids are cancer cell membrane chemoradiation sensitizers. Esterified vitamin E analogues and Ayurvedic Triphala radiosensitize the MCF-7 breast cancer cell line. Curcumin and resveratrol also radiosensitize cancer cells. Withaferin A is synergistic with cisplatin permitting reduced cisplatin doses while maintaining cisplatin’s effectiveness. Conventional cancer treatment associated hand-foot syndrome, hematologic toxicity, mucositis, pain, sleep dysfunction, and overall toxicity respond to several nutraceuticals. Conclusion and significance: The evidence for concurrent nutraceutical use with conventional chemoradiation to reduce conventional chemoradiation doses, and to prevent or limit conventional chemoradiation associated adverse effects exists. In vitro, and murine and human in vivo evidence suggests that nutraceuticals are effective chemoradiation sensitizers and adjuvants, with synergistic potential. Expanded scope positive human trials would facilitate a broader and deeper role for nutraceuticals in integrative cancer treatment.


Nutraceuticals: Chemoradiation Sensitizers and Adverse Effect Resolvers Introduction
Nutraceuticals and phytochemicals play a role in preventing and limiting the adverse sequelae of chemotherapy and radiotherapy, without reducing chemotherapeutic and radiotherapy effectiveness [1][2][3]. Cancer treatment adverse effect amelioration is the primary reason 28.3% of early-stage breast cancer patients in Villejuif, France, use integrative therapies [4]. Although chemoradiation adverse effect treatments form 23.9% of overall European integrative cancer center treatments, 36.1% of Dutch parents of pediatric cancer patients choose integrative treatments for adverse effects of their children's conventional cancer treatments [5,6]. Integrative medicine use is attributed to a 35% reduced health status deterioration, compared to 50% in nonusers [7]. Improved quality of life (QOL) and symptomology are a goal of 75% of Swiss parents seeking integrative cancer treatment for their children, which is consistent with practitioners' goals [5,8]. Relapse prevention, which should include increased treatment efficacy only forms 6.3% of European Integrative Cancer Center therapeutic aims [5]. However, increased bodily ability to fight cancer is the reason why 50.7% of cancer patients use integrative medicine [5].
Genistein and I3C synergistically inhibit human HT-29 colon cancer cells [12]. The cruciferous vegetable derived benzyl-and phenethyl-isothiocyanates irreversibly inhibit N-acetyltransferases thereby decreasing carcinogenic aromatic amines' metabolic activation, and reducing the development of environmental carcinogen triggered cancers [16]. In vitro studies of the phytoalexin isoflavone glyceollin I have achieved a 68% decrease in invasion and an 83% decrease in migration of letrozole-resistant breast cancer cells [17].
Apparently, integrative cancer treatments should have much to offer gynecologic cancer patients. The curative oncologic potential of homeopathy and nutraceuticals is addressed in two separate studies. Therefore, this study seeks to elucidate the extent of nutraceuticals as chemoradiation sensitizers, with an emphasis on gynecologic cancers. Nutraceuticals as adverse effect ameliorators, and nutraceuticals' adverse effects will also be addressed.

Methods
PubMed searches in September 2016 and January 2017, and hand searches in August 2016 and January 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, cancer, cervical cancer, endometrial cancer, ovarian cancer, prevention, and treatment, as shown in Figure 1. Adjuvant characteristics, adverse effects, and chemoradiation sensitization treatments were taken from these searches. These searches retrieved 172 articles, of which 47 articles had a homeopathy focus, 86 articles were focused on phytochemicals, and 39 articles were from content driven hand searches. Cumulatively, 31 articles were excluded for strictly homeopathy related content, 2 articles were editorials, and 1 article was a letter to the editor. There were 15 duplicate articles, 2 redundant articles, and 43 extraneous articles, resulting in a total of 94 excluded and 78 included articles.

Nutraceutical chemoradiation sensitizers
Sensitizing treatments prevent resistance, the innate responses to a treatment that diminish the treatment's effectiveness. Nutraceutical and conventional chemoradiation mechanism of action patterns may be complementary and synergistic, yielding greater treatment effectiveness than the sum effectiveness of each treatment as a single agent. It is biologically plausible that if a DNA damaging treatment and a treatment that prevents DNA repair mechanisms are administered concurrently, the two treatments will be synergistic [10]. Radiation sensitizers that get cells to sensitive parts of the cell cycle are given starting with radiation onset and may be continued after the last radiation treatment. DNA repair inhibitors are also continued post-radiation. Chemosensitizers can also function by tumor microenvironment alteration, creating a hostile environment for cancer stem cells (CSC) [11]. colorectal cancer tumors [18]. Fermented brown rice and bran similarly affect lung cancer [18].
2) PubMed searches in January 2017, search terms "phytochemicals breast or cervical or endometrial or ovarian cancer treatment or prevention" parameters free full text, published from January 1, 2012 (n=86).
3) PubMed search in January 2017, search terms "homeopathy prevention or treatment breast or cervical or endometrial or ovarian cancer," parameters free full text, published from January 1, 2012 (n=6).
Turmeric is synergistic with docetaxel in lung cancer treatment, may improve tolerability of bleomycin and cisplatin, sensitize cancer cells for taxanes (as noted for curcumin above), and reduce resistance to vincas [35]. Similarly, the polyphenol diarylheptanoid hirsutenone from Alnus hirsute var. sibirica tree bark, dosed at 10 μM in vitro, preferentially sensitizes chemoresistant p53 wild-type C13 and OVCAR-433 ovarian cancer cells to cisplatin [36]. Hirsutenone is less effective with p53-defective A2780cp, Hey, Occ-1, and SKOV3 ovarian cancer cell lines [36]. Hirsutenone-dependent, protein kinase B modulated, phosphatidylinositol 3-kinase inhibition is linked to cisplatin and ubiquitin-proteasome-dependent X-linked inhibitor of apoptosis degradation, and increased mitochondria to nucleus translocation of apoptosis-inducing factor [36].
Trametes versicolor (Coriolus or Polyporus), accounts for 25% of Japanese cancer care cost [37]. The Trametes versicolor extract polysaccharide Kureha, gives an HLA type associated proven survival advantage in gastrectomy and esophagectomy patients [38]. Trametes versicolor is also used in integrative breast cancer treatment [39]. Ganoderma lucidum (Reishi or Ling Zhi), contains ganoderic acid and triterpenoids that inhibit cancer cell growth [40]. Viscum album has antitumor activity for hepatocellular carcinoma, and may reduce malignant ascites volume [41]. Teucrium polium L., induced spontaneous regression of alveolar soft part cancer [41].
The Ferula species derived monoterpene conferone is a potent P-glycoprotein inhibitor that reverses MDR when concurrently given with vinblastine to Madin Darby canine kidney cells with the MDR1 gene, which encodes for the efflux protein, P-glycoprotein (MDCK-MDR1), and to the bladder carcinoma 5637-cell line [42]. Without vinblastine, conferone lacks notable anti-tumor activity [42]. Independently, confereone has moderate cytotoxic activity against ovarian cancer CH1 and lung cancer A549 cell lines [42]. The Ferula species derived phytoestrogenic monoterpenes stylosin and tschimgine may have independent anti-cancer activity against the 5637 and MCF-7 cell lines, and have moderate cytotoxic activity against the melanoma SK-MEL-28 cell line [42]. The activity of conferone, stylosin, and tschimgine against CHI lymphoblastoid, A549 alveolar basal epithelial carcinoma, and SK-MEL-28 mutant B-raf and wildtype N-Ras cell lines lacks structure-activity relationships [42]. Therefore, conferone, stylosin, and tschimgine are believed to be chemopreventive and/or chemosensitizing, not directly cytotoxic [42]. The Ferula species derived monoterpenes galbanic acid and farnesiferol may also be potent P-glycoprotein inhibitors to reverse MDR [42].
Pretreatment of the MDA-MB-231 and T47D cell lines with the polyphenol enterolactone radiosensitizes by increasing breast cancer radiation-induced apoptosis, chromosomal aberrations, and micronuclei formation, and reducing radiation-induced DNA damage repair [43]. In vitro studies of melatonin, a polyphenol, show decreased HeLa cell viability [44]. Melatonin synergistically increased the cytotoxicity of cisplatin, 5-fluorouracil, and doxorubicin against HeLa cells by increasing caspase-3 activation, ROS overproduction driven entry into mitochondrial apoptosis, and increased DNA fragmentation [44]. Curcumin also modulates HeLa cells by down regulating Human papilloma virus (HPV) 18 transcription, reversing c-fos and fra-1 expression, and inhibiting AP-1 binding [15].
Withaferin A, from Withnia somnifera (ashwagandha), reduces EOC growth by 70 to 80% and inhibits metastasis by inhibiting CSC [47,48]. In mouse models, Withaferin A in combination with 0.75 the normal dose of cisplatin achieves identical anticancer results as normal dose cisplatin. The in vivo human goal is to prevent or reduce platinum-resistance incidence, which occurs in up to 70% of cases [47]. Withaferin A has synergistic cytotoxicity with doxorubicin for U2OS osteogenic sarcoma and MCF-7 breast cancer cell lines [49]. In vivo xenografts of A2780, A2780/CP70, and CaOV3 epithelial ovarian cancer cell lines treated with Withaferin A and doxorubicin have a 70 to 80% greater reduction in cancer growth than if either agent is used alone, p<0.05 [49]. Withaferin A and doxorubicin at one-ninth the standard dose display time-and dosedependent anti-proliferation and cell death induction that surpasses that of standard dose doxorubicin [49]. Combining doxorubicin with the synthetic curcumin analog HO-3867 increased cytotoxicity, permitting reduced doxorubicin dose, in turn decreasing myocardial toxicity [49]. Curcumin nanocomplexed with doxorubicin overcomes murine in vivo adenosine triphosphate transport associated MDR human and murine acute leukemia, multiple myeloma, ovarian and prostate cancer phenotypes [50]. Curcumin-doxorubicin nanocomplex doses comparable to those at which free doxorubicin and pegylated liposomal doxorubicin cause cardiotoxicity and bone marrow suppression are nontoxic [50].
Milk derived cysteine containing whey proteins are physiologically active beyond the gastrointestinal tract, facilitating antioxidant glutathione synthesis, and phase II detoxification [51]. Mice models show that dairy products reduce tumors by a factor of 0.2 to 0.7 [52]. Soy derived Bowman-Birk inhibitor (BBI) is also a chemoradiation sensitizer, synergistic with cisplatin [51].

Nutraceuticals as cancer preventives
Soy protein intake is inversely associated with breast cancer recurrence and mortality, irrespective of ER status and tamoxifen use [53]. Soy isoflavone intakes of more than 43.75 mg/day have a 0.48 odds ratio (OR) for ER-positive breast cancer incidence, when compared to an intake of less than 18.76 mg/day [54]. Similarly, consumption of soy milk fermented with Lactobacillus casei strain Shirota, four or more times weekly has an OR of 0.65 for ER-positive breast cancer development when compared to an intake of less than 4 times weekly [54]. Soy milk fermented with Streptococcus thermophilus 14085 or Bifidibacterium infantis 14603 inhibits HT-29 epithelial morphology and caco-2 heterogenous epithelial colorectal cancer cell lines [54]. In mice models, soy milk fermented with Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus lactis, or Bifidobacteria inhibited the ER-positive MCF-7 breast cancer [54]. Compared to nonfermented rice bran, ferrulic acid content is increased in rice bran fermented with Saccharomyces boulardii, which decreases lymphoma cell viability [18]. Aspergillus oryzae fermented brown rice decreases bladder, esophageal, and tongue cancer incidence and the number of tongue tumors [18]. Fermented brown rice and bran decrease hepatocellular carcinoma incidence [18]. Lentinus edodes cultured rice bran exo-biopolymer inhibits B16-B16 melanoma [18]. Human epidemiological studies attribute whey-rich dairy products with cancer risk reduction [51].
Phytosterols increase antioxidant enzyme activity and inhibit carcinogen, ROS, and pro-inflammatory cytokine production [52]. Phytosterols are anti-angiogenic. Phytosterols are proapototic by increasing caspase-3 and mitogen activated protein kinase enzymes, decreasing prostaglandin series 2, Bcl2, phosphotydyl inositol-3-phosphate kinase and protein kinase B [52]. The highest quartile phytosterol intake is associated with a 50% reduction (95% CI 0.31 to 0.70) in lung cancer [20]. The highest phytosterol intake is also associated with a 0.33 OR (95% CI 0.17 to 0.65) of stomach cancer incidence [20]. In some Iranian women, after adjustment for confounders, the highest quartile phytochemical index intake (mean 41.6 ± 10.2), is associated with significantly reduced breast cancer risk (OR=0.08, 95% confidence interval [CI] 0.01-0.84) [53]. An in-utero blueberry diet reduces the breast glandular terminal end buds, which are most susceptible to carcinogen transformation [29]. From adolescence through late menopause, berry-polyphenols are antiestrogenic and modulate breast cancer development pathways, including growth factor receptor (GFR) activation [29]. Given the above, apigenin and luteolin rich celery heart, parsley, and thyme; quercetin rich apple and onion; EGCG and ellagic acid rich green tea; ellagic acid rich freeze-dried organic berry; genestein rich soybean; curcumin rich tumeric; and oridonin rich Rabdosia rubescens (Dong Ling Cao) would be recommended as part of an ovarian cancer prevention diet [11]. A diet high in carotenoids, fiber, lignans (coffee, carrots, cucumbers, and strawberries), poultry, stigmasterol (>23 mg per day), and vegetables is known to be chemoprotective for ovarian cancer [55]. Consistent with this, an Italian pooled analysis of 1,411 cases and 3,668 controls, showed that a high vegetable, fruit, nut, fish, unsaturated fats; moderate alcohol; and low meat, dairy, cereals and potatoes diet can reduce endometrial cancer risk to a 0.43 OR, 95% CI 0.34 to 0.56 [56]. However, a prospective study of 112,088 women did not find that a diet high in vegetables or fruits reduced endometrial cancer risk [57].
Tea as a functional food is being studied as a chemopreventive for breast, fibrosarcoma, gastric cancer, glioblastoma, head and neck cancers, neuroblastoma, and prostate cancer as its constituent polyphenols inhibit VEGF, NF-κβ, c-fos and cyclinD1 promoter activity, Bax, and stabilize p53 [21]. The combination of EGCG 200 mg, epigallocatechin 37 mg, and epicatechin 31 mg, as an oral capsule and/or vaginal ointment achieves a mean 69% clearance of HPV-related cervical lesions [15]. Kaemferol, a flavanol polyphenol, is chemopreventive for ovarian cancer by COX-2 and IL-4 inhibition, Src kinase suppression, and NFκβ downregulation [21].

Nutraceuticals for chemoradiation adverse effect resolution
Over 60 nutraceuticals including phytochemicals and vitamins interact with oncologic target molecules [60]. Phytochemicals offer cancer patients clinically (but not statistically) significant pain relief [61]. In non-smokers, antioxidants, including glutathione, and N-acetyl-cysteine, have been shown to reduce chemotherapy toxicity without reducing chemotherapeutic effectiveness [1].
Mistletoe dose-dependently inhibits cell-cycles and triggers apoptosis [62]. Meta-analysis of supportive mistletoe for nonmetastatic colorectal cancer at German and Swiss tumor centers showed fewer adjuvant therapy-related adverse reactions (p<0.001), fewer persisting symptoms (p<0.001), and possible survival benefit [62]. Intravenous mistletoe is recommended for improved overall health, improved tolerance of chemotherapy, and stabilizing pathologic processes [63]. Most studies on mistletoe remedies have not used standardized QOL assessment [64]. When studies on mistletoe remedies have used standardized QOL measures, mistletoe remedies have not been found to provide a significant QOL improvement in comparison to standard care [64].

Nutraceuticals: Adverse effects
Integrative medicine synergism raises conventional cancer treatment efficacy [5]. However, nutraceuticals can also negatively affect conventional cancer treatment [65]. For instance, antioxidant harm has been substantiated for smokers receiving radiotherapy [66]. Lung and prostate cancer risk is significantly raised by vitamin E and high dose β-carotene [21]. However, it is unclear if this risk exists when mixed tocopherols are the vitamin E source, instead of solely α-tocopherols. Nonetheless, these findings are concerning. Moreover, as 40% or fewer integrative medicine users discuss their integrative medicine use with their oncologists, appropriate counseling may not occur [41].
Genistein can be pro-estrogenic in breast cancer, so should be avoided by breast cancer patients [21]. The antiestrogens anastrazole, exemestane, letrozole, and tamoxifen, were used by 38% of Scottish breast cancer patients also taking chamomile, echinacea, garlic, ginseng, grapefruit, pomegranate, or peppermint, all of which affect cytochrome P450 (CYP450) [65]. Ellagic acid is a CYP450 inhibitor capable of reducing anastrazole, exemestane, letrozole, imatinib, and irinotecan levels, while increasing tamoxifen levels [6,65]. Cell repair, including Poly ADP-Ribose Polymerase 1 (PARP-1) mediated cell repair, and signaling pathways can be negatively affected by nutraceuticals [4]. Similarly, excessive anti-angiogenic nutraceutical consumption will inhibit angiogenesis in healthy tissue [21]. Patients prescribed methotrexate or other vitamin antagonists must be counseled against use of nutraceuticals rich in the targeted vitamin [6].
Nuances of nutraceutical and phytochemical use must be understood. Co-administration requirements, dose dependent and whole-body organ system effects should be recognized. For instance, while I3C and DIM are chemoprotective for estrogen-associated cancers, I3C and DIM have been associated with hepatic cancers in rainbow trout [12]. Omega-3-PUFAs should be limited to 5 to 6.9 grams daily due to anticoagulation, glycemic dysfunction, and increased low density lipoprotein (LDL) [67].
In a study of French early-stage breast cancer patients, integrative medicine use was associated with an average 0.6 more important or very important adverse effects than was nonuse [4]. Importantly, integrative medicine use was significantly associated with increased vaginal dryness (p=0.06), fewer hot flushes (p=0.03), and more uncategorized adverse effects (p=0.03) [4]. Minor adverse effects associated with polyphenols are abdominal pain, diarrhea, fatigue, insomnia, and nausea [68]. Adverse effects can be dose and comorbidity dependent. Confusion resulted with consumption of 6 grams daily of green tea extract in an advanced stage prostate cancer patient, but maximum daily green tea extract intake should be 750 mg/day [68]. Grade 4 nephrotoxicity and emesis occur with quercetin dosed at 1,400 mg/m 2 weekly, whereas average daily quercetin intake is about 16 mg/day [68].
Having completed in vitro cell line and in vivo mice trials, apigenin, baicalein, chrysin, genistein, quercetin, and wogonin, should be ready for human trials of VEGF and indoleamine 3,5-dioxygenase-1 inhibition [27]. Because DIM effectively inhibits NF-κβ, which is increased in ovarian cancer [69], DIM could be an ovarian cancer chemosensitization trial candidate. In vivo studies of glyceollin I of more than 40 days duration are needed to ascertain if glyceollin I can reduce tumor weight [17]. Having completed numerous in vitro human cell line studies, and mice and rat in vivo studies, rice bran derivatives should be considered for clinical trials [18]. Poly-catechins such as sinecatechins could be trialed for intravaginal HPV lesions.
Chemoradiation sensitizers candidates should undergo randomized controlled comparative effectiveness studies. For instance, curcumin, hirsutenone, and withaferin A could be studied for cisplatin and/or doxorubicin chemosensitization and synergism equivalence. The curcumin doxorubicin nanocomplex should be considered for human in vivo trials against acute leukemia, multiple myeloma, ovarian and prostate cancer [50]. Curcumin, ellagic acid, tocopherol succinate, and tumeric, could be studied for ionizing radiation sensitization equivalence. Immune response modulation astaxanthin, resveratrol, the Lentinus edodes derived polysaccharide L-II and lentinan, and the polysaccharide fractions of Ganoderma lucidum and Astragalus membranaceus can be investigated for chemosensitization and synergism [70].
These nutraceuticals could be further studied specifically for anti-angiogenic benefits. Anti-angiogenesis could be explored as a factor in mistletoe's colon cancer survival benefit [21].

Cancer prevention
Dietary studies should examine overall diets and the quality of consumed products, instead of portions of diet: Fruits and vegetables in isolation from the overall diet and the quality of the consumed fruits and vegetables may not provide the best data going forward. Consumption of nonorganic "dirty dozen" fruits and vegetables should not have the same chemopreventive effect as consumption of all organic alternatives, including organic frozen berries. Prospective studies of berries and berry polyphenols in high-risk women from the in-utero environment through late menopause could determine if berries and berry polyphenols offer breast cancer primary and secondary chemoprevention [29].
Curcumin, EGCG, genistein, green tea extract, quercetin, red clover, resveratrol and soy should undergo breast, colorectal, and prostate cancer chemoprevention clinical trials in both healthy populations and populations at risk of a primary or secondary malignancy [68]. Retrial of selenium with mixed tocopherols (not all α-) vitamin E is warranted for prostate cancer prevention.

Ongoing trials
There are several trials underway. Chemosensitization trials include immune modulation of prostate cancer by dietary soy [71]. Green tea and EGCG are being investigated for colon carcinogenesis modulation [72]. Combined primary and secondary prevention trials include Phyllanthusmin C, a diphyllin lignin for natural killer cell primary and secondary prevention of acute myeloid leukemia [73]. Primary prevention trials include Silibinin and I3C for inflammation-driven lung cancer chemoprevention [74]. Benzyl isothiocyanate and sulforaphane for breast cancer chemoprevention trial [75,76], and black raspberry phytochemicals for oral cancer chemoprevention [77]. Sulforaphane is also undergoing skin cancer chemoprevention via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and epigenetics trials [78].

Conclusion
The evidence for concurrent nutraceutical use with conventional chemoradiation to reduce conventional chemoradiation doses, and to prevent or limit conventional chemoradiation associated adverse effects exists. In vitro, and murine and human in vivo evidence suggests that nutraceuticals are effective chemoradiation sensitizers and adjuvants, with additive and synergistic potential. Expanded scope positive human trials would facilitate a broader and deeper role for complementary nutraceuticals as part of integrative cancer treatment protocols.