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Managing Treatment Side Effects. Phytochemicals Phytonutrients as Part of Your Cancer Diet. Phytochemicals can be found in brightly colored fruits, such as berries. Sources of phytochemicals The list below is a partial list of phytochemicals found in foods: Allicin is found in onions and garlic.

Allicin blocks or eliminates certain toxins from bacteria and viruses. Anthocyanins are found in red and blue fruits such as raspberries and blueberries and vegetables. They help to slow the aging process, protect against heart disease and tumors, prevent blood clots, and fight inflammation and allergies.

Biflavonoids are found in citrus fruits. Carotenoids are found in dark yellow, orange, and deep green fruits and vegetables such as tomatoes, parsley, oranges, pink grapefruit, and spinach.

Flavonoids are found in fruits, vegetables, wine, green tea, onions, apples, kale, and beans. Indoles are found in broccoli, bok choy, cabbage, kale, Brussel sprouts, and turnips also known as "cruciferous" vegetables.

They contain sulfur and activate agents that destroy cancer-causing chemicals. Isoflavones are found in soybeans and soybean products. Lignins are found in flaxseed and whole grain products. Lutein is found in leafy green vegetables.

It may prevent macular degeneration and cataracts as well as reduce the risk of heart disease and breast cancer. Lycopene is found primarily in tomato products.

When cooked, it appears to reduce the risk for cancer and heart attacks. Phenolics are found in citrus fruits, fruit juices, cereals, legumes, and oilseeds. It is thought to be extremely powerful, and is studied for a variety of health benefits including slowing the aging process, protecting against heart disease and tumors, and fighting inflammation, allergies, and blood clots.

Foods high in phytochemicals Phytochemicals cannot be found in supplements and are only present in food. Broccoli Berries Soynuts Pears Turnips Celery Carrots Spinach Olives Tomatoes Lentils Cantaloupe. Garlic Apricots Onions Seeds Soybeans Green tea Apples Cabbage Brussels sprouts Bok choy Kale Red wine.

Previous Section Next Section. Nationally Recognized. Cancer Fighting Recipe of the Week: Week 3 In honor of Colon Cancer Awareness month , we'll be featuring four colorectal cancer friendly recipes each week during the month of March.

Basil Broccoi Broccoli, cabbage, collard greens, kale, cauliflower and Brussels sprouts are all cruciferous vegetables. Breakfast Recipes. Apple Muffins Baked Oatmeal Banana Bran Muffins Banana-Oatmeal Hot Cakes.

Apoptosis is induced by activation of caspase-3 and inhibiting Akt-phosphorylation. The mechanism of Maslinic acid MSA isolated from Olea europaea is regulated via Bcl-2 inhibition and Bax induction, producing mitochondrial disruption, cytochrome-c release, leading finally to the activation of caspases 9 and caspase 3.

Luteolin O -β-glucoside and its aglycon, luteolin major bio-active constituents of Plantago lanceolata showed DNA topoisomerase I poison activities and Topoisomerase mediated DNA damage might be the possible mechanism which induce apoptosis.

Silibinin SBN extracted from Silybum marianum pretreatment enhance DNA-PK DNA Protein kinase associated kinase activity as well as the physical interaction of p53 with DNA-PK and it preferentially activates the DNA-PK-p53 pathway for apoptosis.

Isosilybin A ISBN extracted from Silybum marianum activates apoptotic machinery in human prostate cancer cells via targeting Akt—NF-kB—AR axis. Mode of action of anticancer activity of phytochemicals present in selected North American medicinal plants.

Currently, natural products, especially plant secondary metabolites such as isoprenoids, phenolics and alkaloids, have been demonstrated to be the leading providers of novel anticancer agents. Thiese important groups of phytochemicals represent a vast majority of chemical groups, including alkaloids, flavonoids, flavonols, flavanols, terpenes and terpenoids, phenols, flavonolignans and steroids.

Potential anticancer properties of these phytochemicals have been shown by both cell culture in vitro methods and animal in vivo methods studies. However, in vitro and in vivo findings should be strengthened by valid human clinical trial data before introducing to the medicine cabinet as natural therapeutics or drugs.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Marianna Kulka. Open access Anticancer Properties of Phytochemicals Present in Medicinal Plants of North America Written By Wasundara Fernando and H.

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Impact of this chapter. Wasundara Fernando Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, Canada H. Introduction Cancer is one of the most severe health problems in both developing and developed countries, worldwide.

Table 1. Medicinal plants with potential anticancer properties grown in North America. Plant Extraction solvent and concentration Type of cancer cell line IC 50 or growth reduction Key findings Ref. Strong in a breast and a prostate cancer cell lines 43 Silybum marianum Milkthistle silybin, a flavonoid Doxorubucin resistant breast MCF-7 , Parental ovarian OVCA , Drug-resistant ovarian A 4.

Table 2. Plant Preparation Animal model used Dosage Key findings Ref. In one treated mouse tumor completely disappeared 14 Eupatorium cannabinum Bonesets Eupatoriopicrin, a sesquiterpene lactone Syngeneic C57B1 female mice i.

Significantly decreased tumor angiogenesis and proliferation and increased apoptosis also. Table 3. Apoptosis was induced by activation of caspase-3 and inhibiting Akt phosphorylation.

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Except for surgery, the primary treatment modalities for breast cancer include radiation, chemotherapy, hormone-based therapies, or targeted therapy [ 78 , 79 ].

Indeed, conventional breast cancer therapies are associated with various adverse effects. Similarly, Nigela sativa L. As stated above, epidemiologic studies conclude that green teas decrease the risk of breast cancer [ 52 ]. The flavonoid epigallocatechingallate EGCG represents the most abundant catechin in green tea and is most likely responsible for the potent biological activity of green tea [ 80 ].

A study by Zhu et al. They demonstrated reduced pain, burning feeling, itching, pulling, and tenderness in breast cancer patients undergoing a mastectomy followed by radiotherapy; besides, no grade 3 or 4 dermatitis was observed in patients receiving EGCG even though receiving the same dose of radiation [ 69 ].

Worsened quality of life QoL and toxicity is common during breast cancer therapy. For example, an impaired nutritional status due to gastro-intestinal toxicity nausea, vomiting during chemotherapy during prolonged time may result in the interruption of the treatment.

Worsening QoL might be related to worsened prognosis and an increase in the risk of recurrence [ 70 ]. However, the nutritional intervention on healthy eating emphasizing fruits, vegetables, grains, among others during the first three cycles of neoadjuvant chemotherapy could minimize clinical involutions during therapy and therapy interruptions.

Anthracycline-based chemotherapy is a backbone of adjuvant breast cancer therapy. However, anthracycline-based chemotherapy is associated with myelosuppression, hair loss, and cardiotoxicity as the most serious side effect.

An administration of phytochemicals or herbs could represent a potent shift to prevent anthracycline-induced cardiotoxicity. Platycodon grandiflorum that has been long used in traditional Chinese medicine to treat cardiovascular diseases prevented acute and chronic cardiac injury induced by anthracycline in early breast cancer patients without compromising the effects of the chemotherapy.

However, the antitumor activity itself was not affected [ 71 ]. Peppermint Mentha piperita extract exerted a significant decrease in the man score of severity of nausea, vomiting, and anorexia in breast cancer patients undergoing chemotherapy compared with the control group [ 72 ].

The subcutaneous injection of mistletoe extracts showed a trend toward less neutropenia and improved pain and appetite loss scores in breast cancer patients undergoing surgery and adjuvant chemotherapy with cyclophosphamide, adriamycin, and 5-fluorouracil.

However, the mistletoe extracts did not affect the frequency of relapse or metastasis within 5 years [ 73 ]. Also, ginger capsules relieved chemotherapy-induced nausea and vomiting in breast cancer patients undergoing chemotherapy [ 74 ].

Oestrogens are crucially involved in the pathogenesis of breast cancer. Musculoskeletal symptoms bone pain, arthralgia, myalgia, carpal tunnel syndrome, trigger finger develop in approximately half of the patients on aromatase inhibitors.

Therefore, aromatase inhibitor-associated musculoskeletal symptoms AIMSS among patients on aromatase inhibitors result in lower QoL and poor adherence to aromatase inhibitors. Indeed, early discontinuation and non-adherence to aromatase inhibitors are related to an increase in mortality of breast cancer patients [ 76 ].

The conventional therapy for AIMSS includes NSAIDs, analgesics, or vitamin D. Still, there is a need for more effective AIMSS management [ 76 ]. Therefore, a pilot study by Martínez et al. Improved musculoskeletal symptoms were observed in patients with AIMSS after an administration of preparation from Chinese medicine Yi Shen Jian Gu granules composed of twelve herbs including Caulis trachelospermi LuoShiTeng , Fructus corni ShanZhuYu , Phryma leptostachya TouGuCao , Poria FuLing , Radix achyranthis bidentatae NiuXi , Radix angelicae sinensis DangGui , Radix paeoniae albae BaiShao , Radix rehmanniae preparatae ShuDiHuang , Rhizoma chuanxiong ChuanXiong , Rhizoma corydalis YanHuSuo , Rhizoma cyperi XiangFu , and Semen cuscutae TuSiZi [ 76 ].

In addition to the side effects of above discussed anticancer strategies, depression, anxiety, and psychosocial distress can occur in up to half of the patients after breast cancer diagnosis and mastectomy. Also, recently emphasized enhanced recovery after surgery ERAS protocols highlight the reduction of opioid analgesics and anxiolytics in patients undergoing microvascular breast reconstruction to reduce risk factors such as an overdose or respiratory distress and reduce comorbid psychological symptoms such as depression and anxiety.

Shammas et al. On the contrary, lavender oil inhaled before breast surgery decreased anxiety in breast cancer patients [ 83 ]. Therefore, low-risk therapeutics of natural origin lowering pain, anxiety, and depression still wait to be identified. In summary, phytochemicals and their mixtures in whole plants exert potent capacity to combat the side effects of current anticancer conventional therapeutic strategies.

However, the clinical research in this area can still be considered poor and requires a comprehensive approach that would allow broad use of phytochemicals in clinical practice.

Conventional anticancer strategies combined with phytochemicals are a promising strategy in the treatment of breast cancer. An early performed clinical trial conducted on ten breast cancer patients undergoing radiotherapy demonstrated the potential of EGCG to enhance radiotherapy demonstrated through decreased levels of vascular endothelial growth factor VEGF , hepatocyte growth factor HGF , and reduced activation of matrix metalloproteinase MMP -9 and MMP-2 in patients receiving radiotherapy plus EGCG compared to patients receiving radiotherapy alone.

Therefore, these results supported the potential of EGCG to serve as an adjuvant against metastatic breast cancer [ 84 ]. Similarly, a double-blinded, randomized controlled clinical trial conducted on fifty-six breast cancer patients revealed that regular onion administration was associated with reduced tumour biomarkers carcinoembryonic antigen CEA and cancer antigen CA during doxorubicin chemotherapy [ 85 ].

In addition, as shown in Table 3 , also recent breast cancer clinical evaluations provided promising results on the efficacy of phytochemicals enhancing the anticancer effect of conventional therapeutics.

A recent randomized controlled pilot trial by Xu et al. The authors concluded that personalization of traditional Chinese medicine could enhance effectiveness lower predictive markers CEA, CA , CA and mitigate side effects cardiac events, less significant reduction of white blood cells, better hepatic function of trastuzumab-containing chemotherapy in HER2-positive breast cancer patients [ 86 ].

Furthermore, a recent comparative, randomized, double-blinded placebo-controlled clinical trial by Saghatelyan evaluated the efficacy and safety of curcumin combined with paclitaxel in advanced, metastatic breast cancer patients. The combination of curcumin and paclitaxel was superior to a paclitaxel-placebo group in terms of objective response rate ORR and physical performance.

Also, curcumin demonstrated no safety issues and no reduction of QoL, and could also be an effective agent to reduce fatigue [ 88 ]. Arglabin is a sesquiterpene guaianolide γ-lactone isolated from Artemisia glabella [ 91 ], an endemic plant of Central Kazakhstan. Fresh yellow onion ameliorated insulin resistance and hyperglycaemia in breast cancer patients during doxorubicin-based chemotherapy.

Thus, a high onion intake represents possible promising synergistic effect in doxorubicin-based chemotherapy [ 90 ]. In , Meng et al. presented a prospective cohort study protocol to evaluate TCM herbs to treat triple-negative breast cancer described by aggressive behaviour, rapid progression, low disease-free survival, and high risk of recurrence and metastasis.

In contrast, secondary objectives include the relationship between QoL and CHM and the correlation between symptoms sleep quality, fatigue, depression, anxiety related to breast cancer and CHM [ 22 ]. The results of the study are to be evaluated. In summary, recent evidence supports the potential of phytochemicals in combination with conventional anticancer agents.

However, expanded comprehensive analyses of the effects of phytochemicals enhancing conventional therapy are necessary to advance breast cancer management and identify better therapeutic strategies. Previously published studies indicate the efficacy of naturally occurring phytochemicals not combined with conventional anticancer therapies in the treatment of breast cancer.

In a phase IB [ 65 ] and IIB dose-escalation trial, Crew et al. highlighted the efficacy of polyphenon E, a green tea extract, to affect biomarkers of tumour growth signalling and angiogenesis in hormone-receptor negative breast cancer.

The extract specifically decreased serum HGF involved in tumour growth, migration, invasion, and VEGF, essential for tumour angiogenesis [ 92 ]. Some other early clinical studies also indicated potent anticancer effects of phytochemicals, based on month dietary changes such as vegetables or fruits among others The dietary changes positively changed LUMA DNA and LINE-1 DNA methylation [ 93 ].

A phenolic compound trans -resveratrol decreased methylation of tumour suppressor RASSF-1α [ 94 ]. In addition, a phase IB dose-escalation study by Perez et al.

In addition to earlier dated studies, more recent clinical evaluations Table 4 evaluated the effects of phytochemicals not combined with conventional anticancer therapies in breast cancer therapy. Moreover, Lazzeroni et al.

Total EGCG content was analysed in all tumour tissues and the concentration was found to be higher than that in normal tissue.

Moreover, free EGCG plasma level correlated with decreased Ki67, a marker of tumour cell proliferation, in tumour tissue. Therefore, these results highlight the increase of EGCG bioavailability through oral GSP and its possible antiproliferative effects in breast cancer patients [ 98 ].

Similarly, a year earlier, Lazzeroni et al. These results can serve as a basis for future clinical evaluation of silybin in breast cancer prevention [ 99 ].

Moreover, long-term pre-diagnosis consumption of soy may result in an increased expression of tumour suppressor microRNA and genes and decreased expression of oncogenes as demonstrated by over-expressed microRNAa-3p and IGF1R and under-expressed KRAS and FGFR4 in TNBC tissues of women with high soy intake [ ].

Moreover, the intake of cruciferous vegetables was associated with a decrease in cell proliferation demonstrated by lower protein expression of Ki67 in ductal carcinoma in situ but not in benign or invasive ductal carcinoma tissues [ ].

In addition, ten herbs of CHM correlated with favourable survival outcomes in metastatic breast cancer patients and the bioinformatic analyses suggest inhibition of HSP90, ERα, and TOP-II related pathway as a potential mechanism of their anticancer action [ 97 ].

The potential anticancer effects of the phytochemicals were also evaluated in breast cancer survivors. Apart from the actual therapy of breast cancer, the understanding of whether post-diagnosis lifestyle characterized by high intake of fruit and vegetable, low energy-dense food, regular physical activity, and healthy body weight also affects the outcome of breast cancer survivors in terms of favourable inflammatory, metabolic, hormonal, and DNA methylation changes decreasing the risk of recurrence.

A short-term dietary intervention on nutrition education exerted efficacy in increasing vegetable and fruit intake in Hispanic breast cancer survivors and altered biomarkers of breast cancer recurrence risk—borderline significant increase in global DNA methylation [ ].

Last but not least, Teixeira et al. Eventually, phenolic acids and urolithin conjugates were the primary metabolites circulating and excreted in the urine. The subjects were classified as high and low urinary metabolite excretors demonstrating interindividual variability in the metabolism of polyphenols.

Despite already published clinical trials, several studies registered at clinicaltrials. gov deals with the potent efficacy of phytochemicals in breast cancer, for example:. The intervention of whole-food, plant-based nutrition in metastatic breast cancer patients ClinicalTrials.

gov Identifier: NCT The response of overweight postmenopausal women with breast cancer to exercise and a plant-based diet ClinicalTrials. The impact of plant extracted natural compounds on breast cancer survival time and regression at stage IV ClinicalTrials. In summary, the above-discussed results of clinical studies or overview of registered clinical trials point to a poor clinical analysis of the potential effects of phytochemicals without the intervention of conventional therapeutics to treat breast cancer.

Extensive metabolism of naturally occurring plant secondary metabolites is considered a limitation of their bioavailability and bioactivity in vivo. The metabolization of phytochemicals occurs in the small and large intestine, and in the liver through associated phase I and II metabolism.

Moreover, the absorption, distribution, metabolism, and elimination of phytochemicals and thus the circulating concentrations, elimination, and tissue exposure to the phytochemical are affected by age, sex, genotype, habitual diet, prescribed medications, and the gut microbiome.

Despite the role of the factors on the side of the individual, the metabolism of phytochemicals is also affected by the structural complexity of phytochemicals alone [ 12 , ].

However, despite the described low bioavailability and bioactivity of phytochemicals in organisms, preclinical in vivo studies demonstrate a potent anticancer efficacy of whole plant food in animal models [ 29 , 35 , 42 , 43 , 48 , ].

Furthermore, some metabolites exert a better physiological function when compared with their precursor [ 12 , ]. Phytochemicals are generally considered safe and well-tolerated but several minor to more severe side effects have been also observed, e. mild gastro-intestinal symptoms, haemolytic anaemia, increased risk of hepatotoxicity, or toxic flavonoid-drug interactions [ 12 , , ].

In humans, phytochemicals exert poor bioavailability and absorption, rapid clearance, resistance, and toxicity. The reduction of mentioned disadvantages by using its nanoparticles is in the infancy of clinical trials but represents a huge potential in future cancer strategies [ ].

Small particle sizes and unique materials used in delivery systems increase the stability and resistance to enzymatic activity in the gastrointestinal tract [ ]. On the other hand, there is still insufficient evidence in the clinical sphere.

Food and Drug Administration FDA approved several liposomes and polymer-based therapeutic nanoparticles for clinical use. The chemotherapeutic nanoparticles such as Doxil® liposome-encapsulated doxorubicin , Abraxane® albumin-bound paclitaxel , and Oncaspar® PEG-Asparaginase have emerged on the pharmaceutical market to date [ ].

Nanomedicine, the alternative drug delivery and improvement of the treatment efficacy, could represent an innovative way in cancer treatment management in the future e.

replacement of current anticancer drugs. Still more detailed clinical studies are needed. Breast cancer is a systemic multi-factorial disease initiated towards increasing health risks such as internal and external stress factors on one hand and, on the other hand, insufficiently effective protection mechanisms against the disease development [ ].

The disease is progressing over years from sub-optimal health conditions to the clinical manifestation of potentially metastatic breast cancer. The time period between a reversible damage to health and irreversible organ damage with cascading complications is the operating timeframe for the primary care in breast cancer prediction and individualized protection.

To this end, the majority of breast cancer cases are preventable that makes primary care to the key point in the paradigm change from the currently applied reactive disease management to the cost-effective 3PM approach [ 6 , 7 ]. Health risk assessment followed by targeted damage-mitigating measures and protection tailored to the individualized patient profile are instrumental to reverse health damage at the level of sub-optimal health [ , ].

As demonstrated above, an application of phytochemicals in the framework of primary care might be a particularly cost-effective approach exemplified by the evidence-based protection against the non-physiologic inflammation [ 35 ] and mitochondrial dysfunction [ ] as well as against the Warburg malignant transformation [ 38 ].

In , Polivka J Jr. et al. The article presented new concepts of 3P medicine focused on the primary care and targeted prevention of one of the most aggressive and devastating BC subtypes, namely the pregnancy-associated breast cancer PABC [ 5 ].

The current article follows the principles and innovation of the distinguished publication and details a protective approach applicable to persons at high PABC risk. Secondary care in breast cancer management is essential to identify affected individuals and to protect them against breast cancer-associated metastatic disease.

Early BC diagnosis utilising non-invasive liquid biopsy approach is highly beneficial to improve individual outcomes [ 8 , ]. Multiomic targets including disease- and stage-specific cell-free nucleic acid patterns and enumeration of circulating tumour cells CTCs density in blood stream are highly recommended for secondary prevention in overall breast cancer management [ 8 ].

For the stratified patients, flavonoids per evidence are of great clinical utility as an effective sensitizer for anti-cancer therapy [ ].

Finally, patients stratified as being highly predisposed to metastatic BC might strongly benefit from the administration of low-toxicity natural anticancer agents targeting specifically CTCs [ ]. Treated cancer patients frequently die of a non-cancer cause well exemplified by stroke.

Stroke in cancer may occur as a severe comorbidity or resulting from the cancer treatment; the described cases are non-bacterial thrombotic endocarditis, hypercoagulability, therapy, or direct tumour compression of blood vessels [ ].

Bang et al. Thrombin generation causing stroke related to coagulopathy is enhanced by both malignancy itself and cancer treatment chemotherapy. Furthermore, a significantly increased risk of stroke may result from accelerated atherosclerosis—the side effect of radiotherapy.

To this end, cancer and stroke share common risks such as vascular dysregulation and ischemic lesions [, 5 , , , ], further pronounced under the cancer treatment conditions [ , ].

The study by Zaorsky et al. concluded that the risk of stroke among cancer patients is twice as high as that of the general population, particularly increasing later on in life. The study demonstrates high plurality of strokes in patients older than 40 years diagnosed with cancer of prostate, breast, and colorectum.

Further breast cancer patients co-diagnosed with sleep disorders are at significantly increased stroke risk [ ]. Consequently, risk assessment and advanced protective strategies in cancer treatments focused on individualized protection against stroke are strongly recommended [ ].

Except cancer, naturally occurring phytochemicals and plant-based diet rich in vegetable, fruit, grains, and olive oil also known as a Mediterranean diet pattern exert efficacy in the protection against stroke, among others [ , ]. The stroke-preventive activity of polyphenols is based on the effects on the cardio- and cerebrovascular system while their efficacy is suggested also when administered after the stroke onset and thus promoting the recovery of stroke patients [ ].

An imbalance between antioxidants and pro-oxidants can result in cell damage, autophagy, apoptosis, and necrosis during stroke. To this end, potent anti-oxidative effects against stress protecting cells from damage are attributed to propolis that is rich in phenolics, flavonoids, and terpenes.

Therefore, stroke-predisposed patients may strongly benefit from the daily supplementation with propolis [ ]. Moreover, findings of the recently performed clinical study demonstrated that moderate habitual intake of flavonoid-rich foods results in lower risk of ischemic stroke [ ].

Similarly, higher consumption of flavonoid-rich food particularly citrus fruit, grapes, strawberries was associated with a decreased risk of stroke in Japanese women [ ].

The above-mentioned clinical trials demonstrating the efficacy of phytochemical-rich food in decreasing the risk of stroke have been conducted on subjects without cancer history [ , ]. Further recent evidence supports biological effects of naturally occurring phytochemicals of potential clinical utility also against the cancer-related stroke.

The flavonoid isoquercetin has been demonstrated to target protein disulfide isomerase required for thrombus formation and thus to improve coagulation markers in advanced cancer patients [ ]. Based on the above discussed protective effects against cardiovascular and cerebrovascular damage among others, here we conclude a potential efficacy of naturally occurring phytochemicals against stroke as a frequent complications and cause of death in the patient cohort with treated cancer.

Follow-up research to the topic is essential to advance secondary care in overall breast cancer management. The motivation of the tertiary care is to advance palliation to the management of chronic disease. The task is highly ambitious, since breast cancer is known as capable to spread metastasis to the lymph nodes, bones, lung, liver, and brain, which are the most frequently reported sites of metastatic disease in BC [ ].

Flavonoids and their nanotechnologically created derivatives have been reported as being of potentially great clinical utility for tertiary care.

Their evident immune-supportive and drug-sensitizing effects which significantly increase sensitivity of malignant cells to anti-cancer therapies up to reversing anti-cancer therapy resistance, are a promising approach complementary to the therapeutic modalities currently applied within the tertiary care [ ].

Several studies demonstrated that cancer patients including breast malignancies are at higher risk of severe illness and related deaths from COVID infection. Managing cancer care under pandemic conditions is challenging. A multidisciplinary approach for optimal care of cancer patients in hospital settings is essential [ ].

Due to their evident anti-inflammatory, anti-bacterial, and anti-viral properties, flavonoids are of great clinical utility in secondary and tertiary care of COVIDinfected cancer patients including breast malignancies [ ].

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We have examined whether Bezielle and its flavonoids induce a common oxidative modification of proteins, carbonylation. Figure 4D shows that Bezielle and scutellarein significant increased the cellular content of carbonylated proteins, and a slight increase was observed with apigenin.

Carthamidin and luteolin did not induce oxidative damage to cellular proteins. The induction of protein carbonylation by Bezielle and scutellarein provides an additional confirmation for the hypothesis that scutellarein is the major cytotoxic agent in Bezielle.

Bezielle induces oxidative DNA damage that is critical for its ability to selectively kill cancer cells [1]. We have examined which of individual Bezielle flavonoids induce DNA damage. MDAMB cells were treated with flavonoids and quantified for two parameters of DNA damage using Comet assay: percent of cells with damaged DNA, and the olive moment the latter reflects the extent of DNA damage per cell.

Isoscutellarein also induced DNA damage but only at higher concentrations not shown. Figure 5A shows that percentage of cells forming comets in presence of scutellarein was gradually increased over time.

This correlates with the increasing levels of ROS induced by scutellarein over time Fig. However, Bezielle induced damage in a much higher percentage of cells already within the first 15—30 minutes Figure 5A. Carthamidin initially induced DNA damage in a higher percentage of cells than scutellarein Fig.

However, no further increase was observed after the first 2 hours, which correlates with the transient nature of carthamidin induced ROS Figure 3. Apparently, carthamidin induced massive but relatively transient DNA damage, which indicates that unlike Bezielle- or scutellarein-induced damage, carthamidin-induced DNA damage could be partially repaired over time.

Chart shows percentages of cells that formed comets. Detection of PARP activity in MDAMB cells treated with Bezielle or scutellarein for 1 and 4 hours. PAR polymers were detected by Western blot analysis.

Induction of nitric oxide by flavonoids. NO was detected using CM-H 2 DAFDA. Cells were treated for 30 minutes or 6 hours. Results are representative of one of the two experiments that produced essentially identical results. Induction of protein nitrosylation by apigenin.

MDAMB cells were treated with flavonoids and stained with a specific antibody to nitrotyrosine followed by a secondary fluorescein-conjugated antibody. Cells treated with apigenin for 2 hours showed an increase in fluorescence gray histogram represents fluorescence of untreated cells; black line corresponds to apigenin-treated.

To examine the role of mitochondrial ROS in DNA damage induced by scutellarein and carthamidin, we have performed comet assays in Rho-0 cells as well as in presence of DPI, and inhibitor of mitochondrial respiration and ROS generation.

In both cases the extent of DNA damage induced by scutellarein and carthamidin was strongly reduced Figure S4. Therefore, analysis of DNA damage induced by two flavonoids also supports the hypothesis that scutellarein is the principal selectively cytotoxic flavonoid in the Bezielle extract.

Carthamidin induces a somewhat transient DNA damage that could contribute to the cytotoxicity of Bezielle. We have examined if scutellarein, like Bezielle, induces activation of PARP. Figure 5B shows that scutellarein activates PARP, but this seems to be delayed compared to Bezielle.

Bezielle activates PARP within 15 minutes of treatment [1] , whereas scutellarein induced appearance of PAR-modified proteins only after 1 hour of treatment. Treatment with apigenin and luteolin predictably had no effect on PARP activity, while carthamidin activated PARP relatively moderately not shown.

We conclude that scutellarein induced DNA damage and activation of PARP are at least in part responsible for the similar activities of Bezielle. We have addressed the possibility that nitric oxide NO could be involved in the induction of DNA damage by Bezielle and flavonoids.

Figure 5C shows that all flavonoids induced a modest increase in NO production in MDAMB cells but not in MCF10A. There was no increase in NO levels over time. Having observed an increase in NO levels induced by flavonoids, we have examined the possibility that mitochondrial superoxide and NO could form peroxynitrite, a highly toxic species of ROS capable of damaging DNA and proteins.

Staining of treated cells with antibodies to nitrotyrosine revealed that apigenin produced a relatively mild increase in levels of cellular nitrotyrosine Fig. We used chemical scavengers of NO and inhibitors of inducible NO synthase in the cytotoxicity assays, and found that they do not protect from cell death induced by Bezielle not shown.

Therefore, induction of NO by flavonoids is unlikely to significantly contribute to the cytotoxicity of Bezielle. Because treatment with Bezielle induces a collapse of redox status in tumor cells that manifests itself, among other changes, in depletion of reduced glutathione GSH , we examined levels of GSH in cells treated with Bezielle flavonoids.

The results of these analyses conducted with MDAMB cells and MCF10A cells are shown in Figure S5. Luteolin had no significant effect on GSH levels in either of the two cell lines.

Apigenin induced a small decrease in GSH in MDAMB cells, but had a much more pronounced negative effect on GSH in MCF10A cells. Scutellarein and carthamidin did not influence levels significantly in MCF10A cells, in agreement with their lack of significant cytotoxicity towards these cells.

However, scutellarein induced a sustained decrease in GSH levels in MDAMB Figure S5C. Carthamidin reduced GSH levels in a transient manner Figure S5C , reminiscent of the transient nature of carthamidin induced ROS and DNA damage Figs.

We conclude from these data that scutellarein has the most profound effect on ROS levels, DNA damage and redox status of MDAMB cells, similar to the total Bezielle extract and indicative of the likely role that this flavonoid plays in the Bezielle cytotoxicity.

The metabolic effects of Bezielle flavonoids were studied using the Seahorse XF96 metabolic flux analyzer that measures the glycolytic activity ECAR, a measure of lactate production and mitochondrial oxygen consumption OCR in a real time non-invasive mode.

Bezielle induces inhibition of both OCR and ECAR Chen et al. Figure 6A shows that flavonoids had different effects on energy pathways in MDAMB cells. The effects of carthamidin were not significant, while scutellarein, similar to Bezielle, suppressed both energy producing pathways.

However, the suppression of ECAR and OCR by scutellarein was not as strong as by Bezielle Figure 6A. ATP levels in cells treated as in B.

We then treated cells with a higher concentration of flavonoids, mainly because cells for the metabolic flux assays are plated at a very high density which in general reduces the inhibitory effects produced by cytotoxic drugs.

The negative effects of apigenin and luteolin on OCR oxygen consumption rate were somewhat more pronounced, and ECAR extracellular acidification rate was largely unaffected by these flavonoids in MDAMB cells Figure 6B.

However, the effects of scutellarein were much stronger at the higher concentration consistent with the dose-dependent cell death induced by scutellarein Figure 2B. Higher concentrations of apigenin and luteolin, but not scutellarein caused a moderate metabolic suppression in MCF10A cells Figure 6B.

Scutellarein was the only flavonoid tested that, in addition to inhibiting mitochondrial respiration, had a very strong inhibitory effect on ECAR selectively in tumor cells. The inhibition of glycolysis by scutellarein was also seen as reduction in PPR proton production rate , an independent measure of glycolytic flux Figure S6A and B.

In addition, as shown in Figure S6C , scutellarein, similar to Bezielle, depletes the mitochondrial reserve capacity measured after injection of FCCP that uncouples respiration from ATP synthesis.

We conclude that in respect to its metabolic effects, scutellarein shows an activity that is very similar to that of the total Bezielle. Inhibition of energy producing pathways in cells obviously could lead to ATP depletion. We examined ATP levels in cells treated with flavonoids for 4 hours.

Figure 6C shows a very significant reduction of ATP in MDAMB cells treated with scutellarein, but not with apigenin and luteolin. The strong depletion of ATP in cells treated with scutellarein and Bezielle was most likely due not only to the inhibition of ATP production, but also to consumption of ATP by the hyper-active PARP Apigenin and luteolin actually induce a transient increase in the ATP levels in MDAMB cells, in agreement with the observed increase in glycolytic activity Figure 6A.

Our unpublished results show that induction of death by apigenin and luteolin proceeds along apoptotic pathway that could involve a transient rise in ATP [8]. Even though the effects of scutellarein and Bezielle on metabolic energy producing pathways in MCF10A cells were mild, the ATP levels in these cells were reduced, most likely to support the energy demands of the DNA damage repair pathway MCF10A show a transient DNA damage after treatment with Bezielle [1] and Chen et al.

Even though scutellarein appears to be the compound responsible for the cancer selective cytotoxicity of Bezielle, the quantitative aspects of this possibility remain uncertain. In addition, we have observed during activity guided isolation that the partially purified fraction depicted in Figure 1 always had a very high activity, while further subfractionation of it into pure compounds did not result in the enrichment of the cytotoxic activity.

This was indicative of the existence of additive or even synergistic effects between two or more flavonoids [9]. A number of combinations of flavonoids were tested for cytotoxic activity and compared to scutellarein alone at the same final concentrations. Addition of carthamidin to scutellarein did not influence the cytotoxicity of the latter in either direction, perhaps because both flavonoids induce DNA damage.

Mixture ALS3,3,4 was less cytotoxic to MDAMB cells than ALS1,1,8 but killed more MCF10A cells than scutellarein alone Figure 7A. This indicates that a combination of several flavonoids could be more active than a single flavonoid in terms of selective cytotoxicity, and that the relative abundance of flavonoids in Bezielle is important in determining the selectivity of the extract.

In particular, increasing the relative amounts of apigenin and luteolin in the combinations with scutellarein leads to loss of tumor selectivity. Mean ± S. Inhibition of OCR and ECAR by scutellarein and mixtures of flavonoids selectively in tumor cells.

Cells were treated for 4 hours with scutellarein alone, or with the mixtures of scutellarein with apigenin and luteolin.

We have addressed the possible basis of the higher selective activity of mixture ALS1,1,8 than of scutellarein alone. We found that ALS1,1,8 mixture was significantly more active in the inhibition of both glycolysis ECAR and respiration OCR in MDAMB31 cells than scutellarein at the same final concentration Figure 7B.

Importantly, combinations of flavonoids did not induce significant changes in metabolic fluxes of MCF10A cells, indicating that even though mixture ALS3,3,4 induced more cell death in MCF10A, this was not due to metabolic inhibition. This was also reflected in the lack of significant changes in ATP levels in MCF10A cells treated with mixtures of flavonoids, whereas a significant reduction in ATP levels was induced by scutellarein and ALS1,1,8 in MDAMB cells Figure 7C.

The mixture ALS3,3,4 did not induce significant loss of ATP in MDAMB cells, perhaps indicating that its cytotoxicity involves apoptosis similar to apigenin and luteolin.

In addition, ALS 3,3,4 no longer had the scutellarein's selectivity towards tumor cells Figure 7A. In conclusion, analysis of the effects of the combination of just three Bezielle flavonoids strongly supports the hypothesis that the selective tumor cell cytotoxicity of Bezielle depends on the multiple flavonoids and their relative amounts in the extract.

The aim of this study was to identify the active phytochemical s responsible for the selective cytotoxic activity of Bezielle. We found that the cytotoxic activity of Bezielle in vitro co-purifies with a distinct chemically defined fraction that contains a number of polyphenolic phytochemicals known as flavonoids.

We set out to analyze Scutellaria flavonoids in a number of assays designed to ascertain whether one or more of the compounds have the following activities determined for Bezielle: a , induction of ROS, particularly of mitochondrial superoxide; b increase in ROS levels over time; c induction of oxidative stress induced selective tumor cell death; d , dependence of cell death induction on presence of respiring mitochondria; e , induction of DNA damage and hyper-activation of PARP; f , disruption of cellular redox status; g , inhibition of both cellular energy-producing pathways.

We identified one flavonoid, scutellarein, which possesses most if not all activities of Bezielle as related to the selective cytotoxicity of the latter. Table 1. From the analysis of Bezielle we have established that all the processes triggered by it in tumor cells could be traced to the induction of high levels of ROS of mitochondrial origin.

Nevertheless, we found that the flavonoids examined here induce various levels of mitochondrial superoxide, but that alone does not confer a selective cytotoxicity to these compounds Table 1. The distinguishing feature of scutellarein is that, like Bezielle, it induces increasing amounts of both mitochondrial superoxide and peroxide.

Probably no less important is the ability of scutellarein to induce increasing levels of DNA damage. Carthamidin at the same concentration also induced DNA damage, but it was transient in nature indicating that it could be repaired.

This could explain, at least partially, why carthamidin, at the same concentration as scutellarein, fails to profoundly affect the energy producing pathways in tumor cells.

Most of the abundant literature published on the activities of apigenin and luteolin describes their antioxidant properties reviewed in [10] , [11] , [12] , but a number of publications to cite just a few of them, [13] , [14] , [15] documents their pro-apoptotic activity in vitro , including towards normal cells [16].

The reason for these contradictory findings could be that the concentrations used in different publications vary greatly [17]. In addition, both apigenin and luteolin generate high levels of peroxide within minutes after treatment but without further increase, while mitochondrial superoxide showed a time-dependent increase Figure 3.

This could indicate that the mitochondrial superoxide induction by these flavones is secondary to the generation of peroxide type ROS from a different cellular source.

It is also possible that some of these observations could be misleading due to the known shortcomings of the available redox-sensitive probes such as used here reviewed in [18]. However, neither elimination of respiration in Rho-0 cells Figure 4A , nor acute treatment with DPI, an inhibitor of complex I [19] , [20] completely prevents induction of ROS by apigenin and luteolin Figure 4A and Figure S2.

Moreover, the limited death induced by apigenin and luteolin, in either tumor or control cells was not preventable by pre-treatment with either NAC or pyruvate, whereas carthamidin, scutellarein and Bezielle induced death was completely abolished Figure 3C and 3D. Pyruvate could act as a mitochondrial fuel, and as such could have a dual effect in Bezielle treated cells, but NAC is an antioxidant.

All these results strongly suggest that even though mitochondria are apparently targeted by apigenin and luteolin, the limited cytotoxicity of these flavonoids does not rely on their pro-oxidant properties.

We have observed a puzzling discrepancy between the high levels of mitochondrial superoxide induced by apigenin and luteolin Figure 3B and lack of DNA damaging or high cytotoxic activity, whereas scutellarein induced lower levels of superoxide that nevertheless lead to damage of nuclear DNA. The fact that scutellarein induced higher levels of peroxide type ROS over time Figure 3A could be relevant to its ability to induce increasing DNA damage.

It is tempting to speculate that scutellarein might target mitochondrial complex III that, unlike complexes I and II, can produce superoxide on both sides of the mitochondrial inner membrane [21]. Complex III derived superoxide could be released directly into cytoplasm, where it is converted to DNA damaging peroxide [21].

Apigenin and luteolin might target complex I, with superoxide released into mitochondrial matrix and subsequently converted to peroxide that is unable to reach the cell nucleus.

This hypothesis is being tested experimentally. We propose that the high selective cytotoxicity of scutellarein relies on the ability of the ROS that it elicits to disrupt the cellular redox balance, to inhibit OXPHOS and induce DNA damage which leads to the inhibition of glycolysis through hyper activation of PARP.

All these activities were observed with the total Bezielle extract Chen et al. Carthamidin, while capable of inducing DNA damage, does not affect glycolysis, at least when used at the same concentrations as scutellarein.

Apigenin and luteolin induce limited apoptotic death that most likely proceeds through the mitochondrial pathway. Therefore, scutellarein was the only flavonoid of the few analyzed here that induced all the cellular responses associated with Bezielle. The most relevant of these seem to be the ability to progressively increase cellular ROS and induce unrepairable DNA damage with grave consequences for cell metabolic activities.

Nevertheless, we have found that addition of small amounts of apigenin and luteolin to scutellarein results in a higher cytotoxicity in tumor cells than scutellarein alone at the same final concentration.

This finding is unexpected for at least two reasons: first, neither apigenin nor luteolin are highly cytotoxic on their own to cancer cell; second, unlike scutellarein, they do not induce either DNA damage or significant inhibition of energy production.

Our unpublished results and many published reports show that these flavones induce apoptotic cell death for example, [15] , [16].

We observed annexin V binding, DNA fragmentation not shown and transient increase in ATP levels 6C in tumor cells treated with apigenin or luteolin, all characteristic for the apoptotic cell death.

Treatment with scutellarein did not induce hallmarks of apoptotic death not shown , but was accompanied by the redox and energy collapse characteristic for necrotic death. We show that combining small amounts of apigenin and luteolin with scutellarein increases suppression of OXPHOS 7B.

We suggest that this could be relevant to the additive effects of these flavones on induction of cell death. These findings explain the difficulties we experienced trying to isolate a single phytochemical from Bezielle that had all the relevant activities of the total extract, with the same potency based on its abundance in the extract.

Scutellarein has all the relevant activities of Bezielle, but the concentration of scutellarein in total extract is much lower than concentrations used in this study. We show that a combination of just three flavonoids from Bezielle had a greater activity than any individual flavonoid indicating that interactions between the flavonoids resulted in higher cytotoxicity.

Our study is not the first to demonstrate positive interactions between flavonoids in respect to cytotoxicity towards cancer cells. Parajuli et al. Positive interactions between different flavonoids have also been reported in regard to their chemopreventive activities [5] , [22] , [23].

The active fraction from Bezielle portrayed in Figure 1 is comprised of at least nine identifiable flavonoids, of which we have analyzed here the most prominent ones.

The other compounds in the flavonoid enriched fraction are being isolated for further analysis. These compounds might have a somewhat limited cytotoxicity of their own, but in the context of the whole extract in combination with scutellarein, they might have an additive or even synergistic effect.

In addition, Bezielle is known to contain much higher concentrations of glucuronidated and glycosylated forms of flavonoids such as scutellarin [25] , and others, that have low intrinsic cytotoxicities in vitro not shown.

An important point, though not relevant to the in vitro studies, is that glucuronidated flavonoids in Bezielle are reduced in vivo to aglycons by gut microflora [26] , which unmasks their latent cytotoxic activity. Therefore, scutellarin and other conjugated flavonoids in Bezielle could serve as a much larger reservoir for active aglycons in vivo.

In summary, this study identified scutellarein as a flavonoid that has most if not all activities relevant to the selective cytotoxicity of Bezielle.

We also show that addition to scutellarein of small amounts of other flavonoids that have limited intrinsic cytotoxicity increases the activity of scutellarein.

We suggest that these interactions between flavonoids could be directly relevant to the high selective cytotoxicity of Bezielle. The latter might depend on its composition of phytochemicals that produce a variety of cellular responses of which some contribute to selective cytotoxicity if Bezielle.

Breast cancer cell line HsT shows a flavonoid sensitivity pattern similar to MDAMB of three experiments. DPI inhibits production of ROS. Generation of ROS in MDAMB cells treated with the indicated compounds or Bezielle for 6 hours in absence or presence of DPI 0.

Cells were analyzed for the peroxide type ROS with DCF-DA and for mitochondrial superoxide with MitoSox. Different mechanisms involved in chemoprevention of different phytochemicals are presented in Table 2. As is presented in Table 2 the success of chemopreventive agents is dependent on their ability to neutralize the precise upstream signals which create different forms of cellular stress, genotoxic damage and redox imbalances.

Different phytochemicals in fruits and vegetables have been detached and recognized which their ability to impede different stages of the carcinogenic process in numerous animal models have been demonstrated 52 , 58 , Recent research has also shown that the reactivation of Nrf2 might be regulated by dietary phytochemicals through epigenetic modifications such as DNA methylation and histone modification.

Block et al. investigated more than epidemiological cases that studied the daily intake of fruits and vegetables effects on different cancers naming lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary In of dietary studies, utilization of fruits and vegetables create a significant protective effect.

Results indicated that the cancer risk decreased due to consumption fruits and vegetables. Significant protection was observed in 24 of 25 studies for lung cancer Fruits consumption was significantly able to create a protective effect in the case of esophagus, oral cavity, and larynx cancers.

Their intake was also protective for cancer of the pancreas and stomach in 26 of 30 studies and for colorectal and bladder cancer in 23 of 38 studies.

Studies to date which demonstrated the ability of common phytochemicals regarding the cancer which they are preventive are presented in Table 3.

The process of carcinogenesis is complex and heterogenous regarding to several combinations of genetic and epigenetic events which occur in an individual cell to create a neoplastic deformation.

Considering different stages of cancer, initiation, promotion and progression, the second step is the main one to be considered for cancer chemoprevention. It has been predicted that more than two-thirds of human cancers could be prevented via proper lifestyle adjustment.

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Resveratrol loaded polymeric micelles for theranostic targeting of breast cancer cells. Green tea, rich in epigallocatechin gallate EGCG , has demonstrated significant reduction of several factors that promote cancer cell proliferation by inhibiting DNA synthesis, de-differentiation and angiogenesis 26, 52, It has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis 50, Resveratrol has demonstrated epigenetic regulatory properties which influence regulate proliferation, cell survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor Caffeic acid and phenethyl ester, as well as inhibiting NF-κB signaling, also have been shown to inhibit cell motility in vitro and inhibit metastasis of tumour models in vivo Luteolin, as well as inhibiting tumour growth and metastasis, inhibits epithelial mesenchymal transition which is a basic biological process related to cancer initiation and development Finally some polyphenols and other phytochemicals are also able to influence cancer via a hormonal mechanism.

Phytoestrogenic compounds, most notably isoflavones and lignans found in soy products, legumes and some cruciferous vegetables, weakly bind to the oestrogen receptor without stimulating proliferation of the cells, yet at the same time blocking the binding of more harmful oestrogens, including those produced endogenously This explains why in the previously mentioned Shanghai Breast Cancer Survival Study, women with the highest intake of isoflavones and flavanones-rich foods had a lower risk of death In men, phytoestrogenic compounds have been shown to affect 5 alpha reductase lowering endogenous testosterone levels.

This may partly explain why men who eat phytoestrogenic foods such as beans and pulses have a lower risk of prostate cancer. If certain foods have anti-cancer effects, then it is not unreasonable to hypothesise that concentrating them into a pill may be a good way to supplement individuals with poor diets or further enhance the benefits in those whoes diets are already adequate.

There are two main categories of supplements commercially available: the first involves chemicals extracted from food, or made synthetically, such as minerals and vitamins; the second involves purifying and concentrating whole foods:.

Vitamins and mineral supplements: The majority of studies, to date, have evaluated extracted chemicals such as vitamins and minerals.

Some have shown a benefit. For example, a recent meta-analysis of studies reported that women who took supplements providing an average daily intake of vitamin C over mg had a reduced risk of breast cancer relapse The SU. MAX study randomised French adults to a single daily capsule of ascorbic acid, vitamin E, beta carotene, selenium and zinc, or a placebo, and found no reduction in mortality or cancer-specific mortality overall 58 , although a further analysis in men found a reduction in the risk of prostate cancer.

The authors postulated that this difference between the sexes was related to French men having a lower baseline micro-nutrient status A major trial of selenium and vitamin supplements in a poor region of China, demonstrated reduced risks of oesophageal cancer; at the time this population was known to have widespread micro-nutrient deficiencies Unfortunately, most other studies of vitamin, minerals and other extracted nutrients have shown no benefit, or have actually shown an increased risk of cancer.

For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer The randomised SELECT study demonstrated an increased prostate cancer incidence with vitamin E and selenium supplementation The negative effects of vitamin E and beta carotene were once again demonstrated in the ATBC study which found them to increase lung cancer risk, although subsequent analysis showed that men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation, and that those with high levels had a higher risk, particularly in smokers This u-shaped distribution of risk was also observed in the EPIC study where those with folate-deficient diets and those with the highest intake both had a higher risk of cancer These data have prompted organisation such as the National Cancer Institute to issue statements stating that long term vitamin and mineral supplements should ideally be given to correct a known deficiency 67 , which is rarely routinely detected unless individuals have self funded micro-nutrient analysis cancernet.

Whole food supplements : More recently academic attention has turned towards the evaluation of concentrated whole food supplements, particularly foods rich in polyphenols and other phytochemicals such as herbs, spices, green vegetables, teas and colourful fruits which have appeared to be beneficial in environmental cohort studies.

Despite some initial encouragement from smaller evaluations, studies of extracted lycopene or genistein given on their own in more scientifically robust analyses have not demonstrate a benefit for either prostate cancer or benign prostatic hypertophy 68, 69, 70 neither were there links with the reduction in the risks of breast cancer with regular intake 5.

Of more concern, a randomised study from Memorial Sloan Kettering reported that serum taken from women who had take very high dose soy supplementation This supports the notion that phytoestrogen foods are healthy, but concentrating them into strong supplements is not recommended.

On the other hand, no study of non-phytoestrogenic foods supplements has shown any detrimental effects on cancer outcomes and some have beneficially influenced progression rates.

For example, a study carried out at John Hopkins involving pomegranate seed extract, found that men taking the supplements had a reduction in PSA progression rate In the Vitamins and Lifestyle VITAL cohort study, a regular intake of grapeseed extract was shown to be linked with a lower risk of prostate cancer 70 , and another small RCT found that a dietary supplement containing isoflavones, plus other phytochemicals and anti-oxidants delayed PSA progression Interestingly one of the most popular supplements, Saw Palmetto , despite an effect in early small studies, showed no benefit for prostate cancer or benign prostatic hypertrophy in the largest randomised evaluation Likewise, another popular supplement, lycopene, despite similar suggestions from smaller non-randomised trials 68, 69 , demonstrated no benefits in a more robust evaluation.

So far, the largest trial analysing phytochemical-rich food extracts was the National Cancer Research Network adopted Pomi-T study This study combined four different food types pomegranate, green tea, broccoli and turmeric in order to provide a wide spectrum of synergistically acting nutrients, whilst at the same time avoiding over-consumption of one particular phytochemical.

It involved two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse, following initial radical interventions. A further analysis of MRI images, demonstrated the cancers size and growth patterns correlated with PSA changes, excluding the possibility that this was just a PSA rather than tumour effect At 6 months, significantly more men opted to remain on surveillance rather than proceeding to expensive radiotherapy, surgery or medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis and erectile dysfunction There are currently over ten, on-going studies registered with the National Institute of Health.

In the UK, the Institute of Preventative Medicine has plans to include the Pomi-T supplement into the next national prostate cancer prevention study.

This study will be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER study, co-ordinated by the Institute of Cancer Research. Further trials are being designed involving men with prostate cancer already on androgen deprivation therapy and individuals with skin, colorectal and bladder cancer.

In the meantime, a trial is passing through the regulatory process to investigate whether the natural anti-inflammatory properties of these ingredients could help joint pains after breast cancer. There is increasingly convincing evidence to show that plant phytochemicals, particularly polyphenols have significant benefits for humans.

Not only do they improve our daily lives by helping our food taste, smell and look appetising, they also reduce our risk of cancer and help people living with and beyond treatments.

Living well programmes, slowly being introduced in the UK, are beginning to highlight the importance of phytochemical-rich diets, along side other lifestyle factors, largely being driving by the National Survivorship Initiative and guidelines from influential organisations such as ASCO. Going a step further and concentrating these foods, or extracted elements of these foods, into nutritional supplements gives an opportunity to boost their beneficial anti-cancer effects, but have their pitfalls.

Studies of concentrated minerals, vitamins and phytoestrogenic supplements have reported detrimental effects. No study has reported detrimental effects of whole, non-phytoestrogenic food supplements and some have reported significant advantages. Hopefully this trend will change, particularly following the success of the Pomi-T study 75 and ongoing studies registered with the National Cancer Institute.

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Ramasamy, K. Clin Cancer Res, ; Deep, G. Integrative Cancer Therapies, ; 6 2 : Gu, M. Carcinogenesis, ; 26 8 : — Cancer Epidemiol Biomarkers Prev, ; Singh, R. Elmore, S. Toxicologic Pathology, ; — Elmorea, S.

and Park, C. Annual Reports In Medicinal Chemistry, ; Dhanalakshmi, S. The Journal of Biological Chemistry, ; 21 — Molecular Carcinogenesis, ; — Giri, A. and Narasu, M. Cytotechnology, 17— Written By Wasundara Fernando and H. Continue reading from the same book View All. Chapter 7 A New Perspective on the Development of Cholestero By Sandhya V.

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