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Specific Chemical Compounds in Citrus Peels Demonstrates Potential Promise in Cancer Prevention

Citrus is a genus of flowering trees and shrubs in the rue family, Rutaceae. Citrus trees and shrubs produce citrus fruits, which include the five different common varieties:

  • Grapefruit
  • Lemon
  • Lime
  • Orange
  • Tangerine

Within each of these common varieties are a number of species. 

List of Citrus Fruits

Citrus peels are very rich in phenolic compounds, such as phenolic acids, flavonoids, limonoids, as wells as carotenoids.  The main source of polyphenols are contained in the citrus peels.  1    A specific class of flavones exist almost ubiquitously in citrus plants named polymethoxylated flavones (PMFs).  These main polymethoxylated flavones in citrus include:

  • nobiletin
  • tangeretin
  • sinesetin
  • 3,5,6,7,8,3′,4′-heptamethoxyflavone
  • 3,5,6,7,3′,4′-hexamethoxyflavone

Six PMFs and three major 5-demethoxyflavones can be extracted from a variety of citrus peels.  2  Accumulative in vitro and in vivo studies indicate protective effects of polymethoxyflavones (PMFs) against the occurrence of cancer. PMFs inhibit carcinogenesis by the following mechanisms:  3

  • blocking the metastasis cascade
  • inhibition of cancer cell mobility in circulatory systems
  • inducing apoptosis
  • antiangiogenesis

Citrus peels also have an abundant source of polyhydroxyl flavonoids (PHFs) which include:

  • hesperidin
  • neohesperidin
  • naringin

Less studied but equally important are the limonoid glucosides, a class of furan-containing triterpenes.  Up to 53 limonoids have been identified and characterized, yet the most important limonoids that are subject to anticancer research include:

  • limonin
  • nomilin
  • nomilinic acid

The anti-cancer activity of citrus peel flavonoids has been studied on several animal models.  The various cancers that have been studied with citrus peel flavonoids include, among others:  4

  • colon cancer
  • lung cancer
  • liver cancer
  • prostate cancer
  • skin cancer

Citrus peels, in addition to cancer prevention and intervention, exhibit other biological functions with various disease states:  5

  • antiatherogenic
  • antimicrobial
  • antithrombotic
  • cardioprotective
  • delayed onset of Alzheimer’s disease  6 
  • hypolipidemia  7 
  • inflammation inhibition  8 
  • neuroprotective  9
  • regulation of metabolic syndrome  10

The Tabs below lists the individual citrus fruit chemical compounds:

Individual Citrus Fruit Chemical Compounds

Carotenoids:
  • Lycopene
  • Beta-Carotene
Furocoumarins:
  • Bergamottin
  • Bergapten
  • Bergaptol
Limonoids
  • Limonin
  • Nomilin
  • Nomilinic acid
Organic Acids:
  • Citric Acid
  • Glycyrrhetinic Acid
Polyphenols:
  • Naringin
  • Naringenin
  • Quercetin
  • Rutin
  • Kaempferol
  • Hesperidin
  • Eriocitrin
  • Nobiletin
  • Tangeritin
  • Diosmin
Terpenoids:
  • Citral
Carotenoids:
  • Beta-Carotene
  • Cryptoxanthin
Limonoids
  • Limonin
  • Nomilin
  • Nomilinic acid
Organic Acids:
  • Citric Acid
  • P-Coumaric Acid
  • Sinapic Acid
Polyphenols:
  • Diosmin
  • Eriocitrin
  • Didymin
  • Hesperidin
  • Rutin
Terpenoids:
  • Limonene
  • Citronellal
  • Citral
Limonoids
  • Limonin
  • Nomilin
  • Nomilinic acid
Polyphenols:
  • Eriocitrin
  • Hesperidin
Terpenoids:
  • Citral
Alkaloids:*
  • Synephrine
  • Hordenine
Amines:*
  • Octopamine
  • N-Methyltyramine
  • Tyramine
Carotenoids:
  • Alpha-Carotene
  • Beta-Carotene
  • Zeaxanthin
  • Lutein
  • Cryptoxanthin
Limonoids
  • Limonin
  • Nomilin
  • Nomilinic acid
Organic Acids:
  • Citric Acid
Polyphenols:
  • Anthocyanidins
  • Cyanidin
  • Dephinidin
  • Tangeretin
  • Hesperidin
Terpenoids:
  • Limonene
  • Citral
* These Alkaloids and Amines are found primarily in the peel of Oranges.
Alkaloids:
  • Synephrine
Carotenoids:
  • Beta-Carotene
  • Lutein
  • Zeaxanthin
Limonoids
  • Limonin
  • Nomilin
  • Nomilinic acid
Organic Acids:
  • Citric Acid
Polyphenols:
  • Nobiletin
  • Tangeretin
  • Hesperidin
Terpenoids:
  • Limonene
  • Carvone

The Table below lists the 7 groups of chemical compounds found in each of the 5 varieties of citrus.

Chemical Compounds Found in Common Citrus Fruits

Chemical CompoundGrapefruitLemonLimeOrangeTangerine
AlkaloidsXX
AminesX
CarotenoidsXXXX
FuranocoumarinsX
LimonoidsXXXXX
Organic AcidsXXX
PolyphenolsXXXXX

This Table specifically excludes the following chemicals found in citrus fruits: carbohydrates, minerals, vitamins, amino acids, enzymes.

The Table below lists the individual chemical compounds in each of the 5 varieties of citrus.

Individual Chemical Compounds in Common Citrus Fruits

Chemical CompoundsGrapefruitLemonLimeOrangeTangerineTotals
Alkaloids:
HordenineX1
SynephrineXX2
Amines:
OctopamineX1
N-MethyltyramineX1
TyramineX1
Carotenoids:
Alpha-CaroteneX1
Beta-CaroteneXXXX4
CryptoxanthinXX2
LuteinXX2
LycopeneX1
ZeaxanthinXX2
Furocoumarins:
BergamottinX1
BergaptenX1
BergaptolX1
Limonoids
LimoninXXXXX5
NomilinXXXXX5
Nomilinic acidXXXXX5
Organic Acids:
Citric AcidXXXX4
Glycyrrhetinic AcidX1
P-Coumaric AcidX1
Sinapic AcidX1
Polyphenols:
AnthocyanidinsX1
CyanidinX1
DephinidinX1
DidyminX1
DiosminXX2
EriocitrinXXX3
HesperidinXXXX4
KaempferolX1
NaringeninX1
NaringinX1
NobiletinX1
QuercetinX1
RutinXX2
TangeritinXXX3
Terpenoids:
CarvoneX1
CitralXXXX4
CitronellalX1
LimoneneXXX3

The Tabs below lists the specific chemical compounds within each chemical group that show evidence of cancer prevention.

Specific Chemical Compounds in Citrus Fruit that May Show Promise for Cancer Prevention

  • Alpha-Carotene
  • Cryptoxanthin
  • Lutein
  • Lycopene
  • Zeaxanthin
Limonoids
  • Limonin
  • Nomilin
  • Nomilinic acid
  • P-Coumaric Acid
  • Anthocyanidins
  • Cyanidin
  • Didymin
  • Diosmin
  • Hesperidin
  • Kaempferol
  • Naringenin
  • Naringin
  • Nobiletin
  • Quercetin
  • Rutin
  • Tangeritin
  • Limonene

The Tabs below lists the published Abstracts and links to various studies within the 5 carotenoids.

Anticancer Properties of Citrus Peel Carotenoids

Alpha-Carotene

CancerAbstractReference
Bladder cancer
We examined the associations between plasma micronutrients and bladder cancer risk, and evaluated the combined effects of carotenoid and cigarette smoke. Our results show protective effects of carotenoids on bladder cancer. They suggest that bladder cancer may be a preventable disease through nutritional intervention, especially in smokers.1
Breast cancer
An inverse association was observed among premenopausal women was for high levels of vitamin A (OR: 0.82, 95%CI: 0.68–0.98, p for trend = 0.01), β-carotene (OR: 0.81, 95% CI 0.68–0.98, p for trend = 0.009), α-carotene (OR: 0.82, 95% CI: 0.68–0.98, p for trend = 0.07), and lutein/zeaxanthin (OR: 0.83, 95% CI 0.68 – 0.99, p for trend = 0.02). An inverse association was not observed among postmenopausal women. Among premenopausal women who reported ever smoking, these results were stronger than among never smokers, although tests for interaction were not statistically significant. Results from this study are comparable to previous prospective studies and suggest that a high consumption of carotenoids may reduce the risk of pre but not post menopausal breast cancer, particularly among smokers.2
Cervical cancer
The mean serum levels of total carotenoids, alpha-carotene, beta-carotene, cryptoxanthin, and lycopene were lower among cases than they were among controls. These findings are suggestive of a protective role for total carotenoids, alpha-carotene and beta-carotene in cervical carcinogenesis and possibly for cryptoxanthin and lycopene as well.3
Colon cancer
To investigate associations between plasma carotenoids, alpha-tocopherol and retinol with colorectal adenomas risk, we measured concentrations in 224 asymptomatic colorectal adenoma cases and 230 population-based controls matched for age and sex. Our findings suggest a protective effect of carotenoids against the development of colorectal adenomas.4
Laryngeal cancer
Significant inverse relations emerged between laryngeal cancer risk and intake of vitamin C (OR = 0.2, for the highest versus the lowest intake quintile; 95% CI: 0.2–0.4), β-carotene (OR = 0.2; 95% CI: 0.2–0.4), α-carotene (OR = 0.3; 95% CI: 0.2–0.5)5
Liver cancer
Potent preventive action of alpha-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by beta-carotene6
Lung cancer
After adjusting for smoking and other covariates, no association was found with lung cancer risk for dietary lycopene or beta-cryptoxanthin intake, whereas dose-dependent inverse associations of comparable magnitude were found for dietary beta-carotene, alpha-carotene, and lutein.7
Neuroblastoma
Analysis by flow cytometry indicated that when GOTO cells were exposed to alpha-carotene, they were arrested in the G0-G1 phase of their cell cycle. However, as the level of the N-myc messenger RNA was recovering, these cells resumed normal cycling. These results indicate that the reduction in the level of the N-myc messenger RNA caused by alpha-carotene is closely linked with G0-G1 arrest.8
Prostate cancer
The adjusted odds ratio for the highest quartiles compared with the lowest were 0.18 (95% CI: 0.08-0.41) for lycopene, 0.43 (95% CI: 0.21-0.85) for α-carotene, 0.34 (95% CI: 0.17-0.69) for β-carotene, 0.15 (95% CI: 0.06-0.34) for α-cryptoxanthin and 0.02 (95% CI: 0.01-0.10) for lutein and zeaxanthin. The dose response relationships were also significant, suggesting that intake of lycopene and other carotenoid rich vegetables and fruits may associate with a reduced risk of prostate cancer.9
Skin cancer
Alpha-carotene was found to have a stronger effect than beta-carotene in suppressing the promoting activity of 12-O-tetradecanoylphorbol-13-acetate on skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated mice.10

Cryptoxanthin

CancerAbstractReference
Breast cancer
Results of this study suggest that the carotenoids beta-cryptoxanthin, lycopene, and lutein/zeaxanthin may protect against breast cancer.1
Cervical cancer
Cryptoxanthin was significantly associated with a lower risk of cervical cancer when examined as a continuous variable. Retinol, lutein, alpha- and gamma-tocopherol, and selenium were not related to cervical cancer risk. Smoking was also strongly associated with cervical cancer. These findings are suggestive of a protective role for total carotenoids, alpha-carotene and beta-carotene in cervical carcinogenesis and possibly for cryptoxanthin and lycopene as well.2
Lung cancer
β-Cryptoxanthin suppresses the growth of immortalized human bronchial epithelial cells and non-small-cell lung cancer cells and up-regulates retinoic acid receptor β expression3
Neuroblastoma
The associations observed in our study suggest that the influence of some antioxidants on survival following a diagnosis of malignant glioma are inconsistent and vary by histology group. Further research in a large sample of glioma patients is needed to confirm/refute our results.4
Prostate cancer
The prostate cancer risk declined with increasing consumption of lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin. Intake of tomatoes, pumpkin, spinach, watermelon and citrus fruits were also inversely associated with the prostate cancer risk. The adjusted odds ratios for the highest versus the lowest quartiles of intake were 0.18 (95% CI: 0.08-0.41) for lycopene, 0.43 (95% CI: 0.21-0.85) for alpha-carotene, 0.34 (95% CI: 0.17-0.69) for beta-carotene, 0.15 (95% CI: 0.06-0.34) for beta-cryptoxanthin and 0.02 (95% CI: 0.01-0.10) for lutein and zeaxanthin. 5

Lutein

CancerAbstractReference
Bladder cancer
Our results show protective effects of carotenoids on bladder cancer. They suggest that bladder cancer may be a preventable disease through nutritional intervention, especially in smokers.1
Breast cancer
An inverse association was observed among premenopausal women was for high levels of vitamin A (OR: 0.82, 95%CI: 0.68–0.98, p for trend = 0.01), β-carotene (OR: 0.81, 95% CI 0.68–0.98, p for trend = 0.009), α-carotene (OR: 0.82, 95% CI: 0.68–0.98, p for trend = 0.07), and lutein/zeaxanthin (OR: 0.83, 95% CI 0.68 – 0.99, p for trend = 0.02).2
Colon cancer
Lutein was inversely associated with colon cancer in both men and women [odds ratio (OR) for upper quintile of intake relative to lowest quintile of intake: 0.83; 95% CI: 0.66, 1.04; P = 0.04 for linear trend]. The greatest inverse association was observed among subjects in whom colon cancer was diagnosed when they were young (OR: 0.66; 95% CI: 0.48, 0.92; P = 0.02 for linear trend) and among those with tumors located in the proximal segment of the colon (OR: 0.65; 95% CI: 0.51, 0.91; P 3
Liver cancer
Lutein presented inhibitory actions during promotion but not initiation of hepatocarcinogenesis, being classified as a suppressing agent. This reinforces lutein as a potential agent for liver cancer chemoprevention.4
Lung cancer
Protective effects on lung cancer incidence were found for lutein + zeaxanthin, beta-cryptoxanthin, folate, and vitamin C. Other carotenoids (alpha-carotene, beta-carotene, and lycopene) and vitamin E did not show significant associations.5
(Non-Hodgkin’s) Lymphomas
Higher intakes of vegetables, lutein and zeaxanthin, and zinc are associated with a lower non-Hodgkin lymphoma (NHL) risk.6
Ovarian cancer
Micronutrients, specifically ss-carotene, lycopene, zeaxanthin, lutein, retinol, alpha-tocopherol, and gamma-tocopherol, may play a role in reducing the risk of ovarian cancer.7
Prostate cancer
Results demonstrated that both lycopene, in an alpha -cyclodextrin water soluble carrier, and lutein inhibited malignant AT3 cells in a concentration and time-dependent manner. 8
Skin cancer
The results of the photocarcinogenesis experiment were increased tumor-free survival time, reduced tumor multiplicity and total tumor volume in lutein/zeaxanthin-treated mice in comparison with control irradiated animals fed the standard diet. These data demonstrate that dietary lutein/zeaxanthin supplementation protects the skin against UVB-induced photoaging and photocarcinogenesis.9

Lycopene

CancerAbstractReference
Breast cancer
The inhibition of cell growth by lycopene was accompanied by slow down of cell-cycle progression from G1 to S phase. Moreover, the carotenoids inhibited estrogen-induced transactivation of ERE that was mediated by both estrogen receptors (ERs) ERalpha and ERbeta. The possibility that this inhibition results from competition of carotenoid-activated transcription systems on a limited pool of shared coactivators with the ERE transcription system was tested.1
Cervical cancer
 Increasing concentrations of serum lycopene were negatively associated with CIN1, CIN3 and cancer, with odds ratios (OR) (95% CI) for the highest compared to the lowest tertile of 0.53 (0.27-1.00, p for trend = 0.05), 0.48 (0.22-1.04, p for trend = 0.05) and 0.18 (0.06-0.52, p for trend = 0.002), respectively, after adjusting for confounding variables and HPV status.2
Colon cancer
Lycopene treatment suppressed Akt activation and non-phosphorylated beta-catenin protein level in human colon cancer cells. Immunocytochemical results indicated that lycopene increased the phosphorylated form of beta-catenin proteins. These effects were also associated with reduced promoter activity and protein expression of cyclin D1. Furthermore, lycopene significantly increased nuclear cyclin-dependent kinase inhibitor p27(kip)abundance and inhibited phosphorylation of the retinoblastoma tumor suppressor protein in human colon cancer cells.3
Endometrial cancer
In contrast to cancer cells, human fibroblasts were less sensitive to lycopene, and the cells gradually escaped growth inhibition over time. In addition to its inhibitory effect on basal endometrial cancer cell proliferation, lycopene also suppressed insulin-like growth factor-I-stimulated growth. Insulin-like growth factors are major autocrine/paracrine regulators of mammary and endometrial cancer cell growth. Therefore, lycopene interference in this major autocrine/paracrine system may open new avenues for research on the role of lycopene in the regulation of endometrial cancer and other tumors.4
Esophageal cancer
This review of previous epidemiological studies found that high blood lycopene levels are associated with a reduced risk of esophageal cancer.5
Gliomas
Addition of nutrition supplements such as lycopene may have potential therapeutic benefit in the adjuvant management of high-grade gliomas.6
Liver cancer
The invasion of SK-Hep1 cells treated with lycopene was significantly reduced to 28.3% and 61.9% of the control levels at 5 microM and 10 microM lycopene, respectively (P 7
Leukemia
The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibited a synergistic effect on cell proliferation and differentiation and an additive effect on cell cycle progression. Such synergistic antiproliferative and differentiating effects of lycopene and other compounds found in the diet and in plasma may suggest the inclusion of the carotenoid in the diet as a cancer-preventive measure.8
Lung cancer
In conclusion, lycopene may mediate its protective effects against smoke-induced lung carcinogenesis in ferrets through up-regulating IGFBP-3 and down-regulating phosphorylation of BAD, which promote apoptosis and inhibit cell proliferation.9
Mouth cancer
The results of the present study further support the hypothesis that carotenoids in general, and lycopene in particular, may be effective anticarcinogenic agents in oral carcinogenesis.10
Ovarian cancer
Micronutrients, specifically ss-carotene, lycopene, zeaxanthin, lutein, retinol, alpha-tocopherol, and gamma-tocopherol, may play a role in reducing the risk of ovarian cancer.11
Pancreatic cancer
After adjustment for age, province, BMI, smoking, educational attainment, dietary folate, and total energy intake, lycopene, provided mainly by tomatoes, was associated with a 31% reduction in pancreatic cancer risk among men [odds ratio (OR) = 0.69; 95% CI: 0.46-0.96; P = 0.026 for trend] when comparing the highest and lowest quartiles of intake. Both beta-carotene (OR = 0.57; 95% CI: 0.32-0.99; P = 0.016 for trend) and total carotenoids (OR = 0.58; 95% CI: 0.34-1.00; P = 0.02 for trend) were associated with a significantly reduced risk among those who never smoked. The results of this study suggest that a diet rich in tomatoes and tomato-based products with high lycopene content may help reduce pancreatic cancer risk.12
Prostate cancer
We report the inhibitory effect(s) of lycopene in primary prostate epithelial cell (PEC) cultures, and the results of a pilot phase II clinical study investigating whole-tomato lycopene supplementation on the behavior of established CaP, demonstrating a significant and maintained effect on prostate-specific antigen velocity over 1 year.13

Zeaxanthin

CancerAbstractReference
Breast cancer
Carotenoids could inhibit the proliferation of human beast cancer MCF-7 cell line in vitro and the action of carotenoids may be worked through different pathways.1
Lung cancer
Inverse associations with carotenes, lutein + zeaxanthin, and beta-cryptoxanthin seemed to be limited to small cell and squamous cell carcinomas. Only folate and vitamin C intake appeared to be inversely related to small cell and squamous cell carcinomas and adenocarcinomas. Folate, vitamin C, and beta-cryptoxanthin might be better protective agents against lung cancer in smokers than alpha-carotene, beta-carotene, lutein + zeaxanthin, and lycopene.2
Neuroblastoma
Zeaxanthin strongly induced apoptosis in neuroblastoma cells. Consistent with this finding, zeaxanthin did not inhibit LOX activity. Zeaxanthin is a remarkable dietary factor that is able to induce apoptosis in neuroblastoma cells while being able to prevent apoptosis in healthy cells.3

The Tabs below lists the published Abstracts and links to various studies within the 3 limonoids.

Anticancer Properties of Citrus Peel Limonoids

Limonin

CancerAbstractReference
Colon Cancer
The current study was an attempt to elucidate the mechanism of human colon cancer cell proliferation inhibition by limonin and limonin glucoside (LG) isolated from seeds of Citrus reticulata. Results of the current study provide compelling evidence on the induction of mitochondria mediated intrinsic apoptosis by both limonin and LG in cultured SW480 cells for the first time.1

Nomilin

CancerAbstractReference
Inhibits tumor-specific angiogenesis
These data clearly demonstrate the antiangiogenic potential of nomilin by downregulating the activation of MMPs, production of VEGF, NO and proinflammatory cytokines as well as upregulating IL-2 and TIMP.1
Inhibits chemical-induced carcinogenesis
Limonin and nomilin, two of the most abundant limonoids, have been found to inhibit chemical-induced carcinogenesis. Both compounds are inducers of glutathione S-transferase, a major detoxifying enzyme system. The increased enzyme activity was correlated with the ability of these compounds to inhibit carcinogenesis.2
Melanoma
Nomilin is a triterpenoid present in common edible citrus fruits with putative anticancer properties. In this study, the authors investigated the antimetastatic potential of nomilin and its possible mechanism of action. Metastasis was induced in C57BL/6 mice through the lateral tail vein using highly metastatic B16F-10 melanoma cells. Administration of nomilin inhibited tumor nodule formation in the lungs (68%) and markedly increased the survival rate of the metastatic tumor-bearing animals. 3

Nomilinic acid

CancerAbstractReference
Induces apoptosis
No significant effects were observed on growth of the other cancer cell lines treated with the four individual limonoids at 100 micrograms/ml. At 100 micrograms/ml, the limonoid glucoside mixture demonstrated a partial inhibitory effect on SKOV-3 cancer cells. With use of flow cytometry, it was found that all the limonoid samples could induce apoptosis in MCF-7 cells at relatively high concentrations (100 micrograms/ml). 1
Breast cancer
Although most of the limonoids showed anti-aromatase activity, the inhibition of proliferation was not related to the anti-aromatase activity. On the other hand, the anti-proliferative activity was significantly correlated with caspase-7 activation by limonoids. Our findings indicated that the citrus limonoids may have potential for the prevention of estrogen-responsive breast cancer (MCF-7) via caspase-7 dependent pathways.2
Neuroblastoma
We conclude that citrus limonoid glucosides are toxic to SH-SY5Y cancer cells. Cytotoxicity is exerted through apoptosis by an as yet unknown mechanism of induction. Individual limonoid glucosides differ in efficacy as anticancer agents, and this difference may reside in structural variations in the A ring of the limonoid molecule.3

The Table below lists the published Abstract and links to the studies on P-Coumaric acid.

P-Coumaric Acid

CancerAbstractReference
Colon cancer
We demonstrate that two hydroxycinnamic acids, (E )-ferulic acid and (E )-p-coumaric acid, have the ability to protect against oxidative stress and genotoxicity in cultured mammalian cells. They also show the ability to reduce the activity of the xenobiotic metabolising enzyme, cytochrome P450 1A, and downregulate the expression of the cyclooxygenase-2 enzyme. At equitoxic doses, their activities are equal to or superior to that of the known anticarcinogen, curcumin. The hydroxycinnamic acids are both important components of plant cell walls in certain plant foods. It is known that the action of microbial hydroxycinnamoyl esterases can lead to the release of hydroxycinnamic acids from ester-linkages to cell wall polysaccharides into the human colon. 1
Results depicted that p-Coumaric acid inhibited the growth of colon cancer cells by inducing apoptosis through ROS-mitochondrial pathway.2

The Table below lists the published Abstracts and links to the various studies on Limonene.

Limonene

CancerAbstractReference
Breast Cancer
The blocking chemopreventive effects of limonene and other monoterpenes during the initiation phase of mammary carcinogenesis are due to the induction of Phase II carcinogen-metabolizing enzymes, resulting in carcinogen detoxification. The post-initiation phase chemopreventive and chemotherapeutic activities of monoterpenes may be due to the induction of tumor cell apoptosis, tumor redifferentiation, and/or inhibition of the post-translational isoprenylation of cell growth-regulating proteins.1
Colon Cancer
Diet-cancer and diet-cardiovascular disease interrelationships may be explained by the mevalonate-suppressive action of isoprenoid end products of plant secondary metabolism. Assorted monoterpenes, sesquiterpenes, carotenoids and tocotrienols posttranscriptionally down regulate 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, a key activity in the sterologenic pathway. 2
Leukemia
The results showed that D-limonene (D-L) inhibited HL-60 and K562 cell growth in a dose- and time-dependent manner with the IC50 of 0.75 mmol/L similarly, D-L induced apoptosis of HL-60 and K562 cells, and expression of bcl-2 gene was down regulated by D-L in a concentration-dependent manner in HL-60 cells.3
Liver Cancer
Monoterpenes are nonnutritive dietary components found in the essential oils of citrus fruits and other plants. A number of these dietary monoterpenes have antitumor activity. For example, d-limonene, which comprises >90% of orange peel oil, has chemopreventive activity against rodent mammary, skin, liver, lung and forestomach cancers. 4
Lung Cancer
D-limonene given p.o. 1 h prior to NNK administered i.p. again showed pronounced inhibition of pulmonary adenoma formation. This study provides additional data demonstrating that non-nutrient constituents of the diet can inhibit carcinogen-induced neoplasia when administered at a short time interval prior to carcinogen challenge.5
Lymphomas
Results showed that limonene exhibited antiproliferative action on tumoral lymphocytes exerting a decrease in cell viability that was related to apoptosis induction and to the increase in NO levels at long incubation times. At short times and depending on its concentration, limonene arrested cells in different phases of the cell cycle, related to NO production.6
Skin Cancer
Monoterpenes are nonnutritive dietary components found in the essential oils of citrus fruits and other plants. A number of these dietary monoterpenes have antitumor activity. For example, d-limonene, which comprises >90% of orange peel oil, has chemopreventive activity against rodent mammary, skin, liver, lung and forestomach cancers.7
Squamous Cell Carcinoma
This is the first study to explore the relationship between citrus peel consumption and human cancers. Our results show that peel consumption, the major source of dietary d-limonene, is not uncommon and may have a potential protective effect in relation to skin squamous cell carcinoma (SCC). 8
Stomach Cancer
D-limonene has antiangiogenic and proapoptotic effects on gastric cancer, thereby inhibits tumor growth and metastasis. Combination of d-limonene with cytotoxic agents may be more effective.9

The Table below lists the published Abstract and link to the studies on Limonin.

Limonin

CancerAbstractReference
Colon Cancer
The current study was an attempt to elucidate the mechanism of human colon cancer cell proliferation inhibition by limonin and limonin glucoside (LG) isolated from seeds of Citrus reticulata. Results of the current study provide compelling evidence on the induction of mitochondria mediated intrinsic apoptosis by both limonin and LG in cultured SW480 cells for the first time.1

The Tabs below lists the published Abstracts and links to various studies within the 6 polyphenols of citrus peels.  (Part 1 of 2)

Anticancer Properties of Citrus Peel Polyphenols (Part 1 of 2)

Anthocyanidins

CancerAbstractReference
Breast cancer
At 200 μg/mL, cyanidin, delphinidin and petunidin inhibited the breast cancer cell growth by 47, 66 and 53%, respectively. This is the first report of tumor cell proliferation inhibitory activity by anthocyanidins.1
Non-Hodgkin lymphoma
Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes--diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146). A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.2

Cyanidin

CancerAbstractReference
Colon cancer
Anthocyanins and cyanidin also reduced cell growth of human colon cancer cell lines HT 29 and HCT 116. The IC(50) of anthocyanins and cyanidin was 780 and 63 microM for HT 29 cells, respectively and 285 and 85 microM for HCT 116 cells, respectively. These results suggest that tart cherry anthocyanins and cyanidin may reduce the risk of colon cancer.1
Leukemia
These results indicate that cyanidin-3-rutinoside has the potential to be used in leukemia therapy with the advantages of being widely available and selective against tumors.2

Didymin

CancerAbstractReference
Lung cancer
Importantly, a novel chemotherapeutic agent for the treatment of non-small-cell lung cancer, and is supported by animal studies which have shown didymin delay the tumor growth in nude mice. Our study reports here for the first time that the activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of didymin in A549 and H460 cells.1

Diosmin

CancerAbstractReference
Bladder cancer
The chemopreventive effects of 2 flavonoids (diosmin and hesperidin) on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary-bladder carcinogenesis were examined in male ICR mice.  Feeding of the test compounds, singly or in combination, during both phases caused a significant reduction in the frequency of bladder carcinoma and preneoplasia. Dietary administration of these compounds significantly decreased the AgNOR count and the BUdR-labeling index of various bladder lesions. These findings suggest that the flavonoids diosmin and hesperidin, individually and in combination, are effective in inhibiting chemical carcinogenesis of the bladder, and that such inhibition might be partly related to suppression of cell proliferation.1
Colon cancer
These results indicate that diosmin and hesperidin, both alone and in combination, act as a chemopreventive agent against colon carcinogenesis, and such effects may be partly due to suppression of cell proliferation in the colonic crypts, although precise mechanisms should be clarified.2
Esophageal cancer
These findings suggest that diosmin and hesperidin supplementation, individually or in combination, is effective in inhibiting the development of oesophageal cancer induced by MNAN when given during the initiation phase, and such inhibition might be related to suppression of increased cell proliferation caused by MNAN in the oesophageal mucosa.3
Mouth cancer
Diosmin, the 7-rutinoside of diosmetin, surprisingly, was more potent and effective than diosmetin. In contrast, quercitrin, the 3-rhamnoside of quercetin, showed no effect and only minimal cellular uptake and no hydrolysis. In summary, dietary flavonoid glycosides may exert cellular effects in the oral cavity, but this varies greatly with the nature of the glycoside.4

Hesperidin

CancerAbstractReference
Bladder cancer
Dietary administration of these compounds significantly decreased the AgNOR count and the BUdR-labeling index of various bladder lesions. These findings suggest that the flavonoids diosmin and hesperidin, individually and in combination, are effective in inhibiting chemical carcinogenesis of the bladder, and that such inhibition might be partly related to suppression of cell proliferation.1
Breast cancer
Two citrus flavonoids, hesperetin and naringenin, are found in orange and grapefruit, respectively. An experimental study has shown that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, widely distributed in other foods2
Cervical cancer
This study shows that hesperetin exhibits a potential anticancer activity against human cervical cancer cell lines in vitro through the reduction in cell viability and the induction of apoptosis. Altogether, these data sustain our contention that hesperetin has anticancer properties and merits further investigation as a potential therapeutic agent.3
Colon cancer
Inhibition of Colonic Aberrant Crypt Formation by the Dietary Flavonoids (+)-Catechin and Hesperidin4
Esophageal cancer
These findings suggest that diosmin and hesperidin supplementation, individually or in combination, is effective in inhibiting the development of oesophageal cancer induced by MNAN when given during the initiation phase, and such inhibition might be related to suppression of increased cell proliferation caused by MNAN in the oesophageal mucosa.5
Leukemia
The apoptotic activity of CME was significantly attenuated by Akt augmentation. In conclusion, this study suggested that Citrus aurantium L. (CMEs) should induce caspase-dependent apoptosis at least in part through Akt inhibition, providing evidence that CMEs have anticancer activity on human leukemia cells.6
Lung cancer
Hesperidin (25 mg/kg body weight) supplementation effectively counteracted all the above changes and restored cellular normalcy, indicating its protective role during B(a)P-induced lung cancer.7
Mouth cancer
These findings suggest that supplementation with the flavonoids diosmin and hesperidin, individually and in combination, is effective in inhibiting the development of oral neoplasms induced by 4-NQO, and such inhibition might be related to suppression of increased cell proliferation caused by 4-NQO in the oral mucosa.8
Prostate cancer
t is concluded that hesperidin can inhibit the proliferation of breast cancer cells through mechanisms other than antimitosis and it is suggested that hesperidin be further investigated for the possible interaction with androgenic receptors and involvement in signaling pathway after receptor binding in prostate cancer cells through future research.9

Kaempferol

CancerAbstractReference
Breast cancer
This paper also presents in vivo data of primary breast cancer prevention by individual compounds and whole berries. Finally, a possible role for berries and berry compounds in the prevention of breast cancer and a perspective on the areas that require further research are presented. 1
Glioblastoma Multiforme
Importantly, kaempferol potentiated the toxic effect of chemotherapeutic agent doxorubicin by amplifying ROS toxicity and decreasing the efflux of doxorubicin. Because the toxic effect of both kaempferol and doxorubicin was amplified when used in combination, this study raises the possibility of combinatorial therapy whose basis constitutes enhancing redox perturbation as a strategy to kill glioma cells.2
Leukemia
Some simple and polyphenols found in honey, namely, caffeic acid (CA), caffeic acid phenyl esters (CAPE), Chrysin (CR), Galangin (GA), Quercetin (QU), Kaempferol (KP), Acacetin (AC), Pinocembrin (PC), Pinobanksin (PB), and Apigenin (AP), have evolved as promising pharmacological agents in treatment of cancer. In this review, we reviewed the antiproliferative and molecular mechanisms of honey and above-mentioned polyphenols in various cancer cell lines.3
Lung cancer
Certain flavonoid compounds, including epicatechin, catechin, quercetin, and kaempferol, were associated inversely with lung cancer among tobacco smokers, but not among nonsmokers. Further studies of these associations may be warranted.4
Ovarian cancer
Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted.5
Pancreatic cancer
Total flavonols, quercetin, kaempferol, and myricetin were all associated with a significant inverse trend among current smokers (relative risks for the highest vs. lowest quartile = 0.41, 0.55, 0.27, 0.55, respectively) but not never or former smokers. This study provides evidence for a preventive effect of flavonols on pancreatic cancer, particularly for current smokers.6
Stomach cancer
A case controlled study found that “consumption of kaempferol-containing foods was associated with a reduced gastric cancer risk”7

The Tabs below lists the published Abstracts and links to various studies within the 6 polyphenols of citrus peels.  (Part 2 of 2)

Anticancer Properties of Citrus Peel Polyphenols (Part 2 of 2)

Naringenin

CancerAbstractReference
Breast cancer
Collectively, our findings suggest that naringenin inhibits the proliferation of MCF-7 cells via impaired glucose uptake. Because a physiologically attainable dose of 10 µM naringenin reduced insulin-stimulated glucose uptake by nearly 25% and also reduced cell proliferation, naringenin may possess therapeutic potential as an anti-proliferative agent.1
Colon cancer
The ability of dietary apigenin and naringenin to reduce HMACF, lower proliferation (naringenin only) and increase apoptosis may contribute toward colon cancer prevention. However, these effects were not due to mitigation of iNOS and COX-2 protein levels at the ACF stage of colon cancer.2
Melanoma
everal polyphenolic compounds were tested for the inhibition of lung metastasis induced by B16F10 melanoma cells in mice. Oral administration of polyphenols such as curcumin and catechin at concentrations of 200 nmol/kg body weight were found to inhibit the lung metastasis maximally as seen by the reduction in the number of lung tumor nodules (80%). Other polyphenols which inhibited the lung tumor nodule formation were rutin (71.2%), epicatechin (61%), naringin (27.2%) and naringenin (26.1%). 3
Prostate cancer
As part of a systematic study of the effects of phytochemicals beyond antioxidation on cancer prevention, we investigated whether naringenin (NR), a citrus flavonoid, stimulates DNA repair following oxidative damage in LNCaP human prostate cancer cells. In conclusion, the cancer-preventive effects of citrus fruits demonstrated in epidemiological studies may be due in part to stimulation of DNA repair by NR, which by stimulating BER processes may prevent mutagenic changes in prostate cancer cells.4

Naringin

CancerAbstractReference
Breast cancer
Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA-MB-435 These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods.  1
Lung cancer
To investigate the possible relationship between intake of flavonoids-powerful dietary antioxidants that may also inhibit P450 enzymes-and lung cancer risk, we conducted a population-based, case-control study in Hawaii. If replicated, particularly in prospective studies, these findings would suggest that foods rich in certain flavonoids may protect against certain forms of lung cancer and that decreased bioactivation of carcinogens by inhibition of CYP1A1 should be explored as underlying mechanisms.2
Melanoma
Oral administration of polyphenols such as curcumin and catechin at concentrations of 200 nmol/kg body weight were found to inhibit the lung metastasis maximally as seen by the reduction in the number of lung tumor nodules (80%). Other polyphenols which inhibited the lung tumor nodule formation were rutin (71.2%), epicatechin (61%), naringin (27.2%) and naringenin (26.1%). 3
Mouth cancer
The results with naringin and naringenin show that both of these flavonoids significantly lowered tumor number [5.00 (control group), 2.53 (naringin group), and 3.25 (naringenin group)]. Naringin also significantly reduced tumor burden [269 mm(3)(control group) and 77.1 mm(3)(naringin group)]. The data suggest that naringin and naringenin, 2 flavonoids found in high concentrations in grapefruit, may be able to inhibit the development of cancer.4

Nobiletin

CancerAbstractReference
Colon cancer
Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. 1
Leukemia
In vitro effects of medicinal plant extracts from the pericarpium of Citrus reticulata (cv Jiao Gan) (PCRJ) on the growth and differentiation of a recently characterized murine myeloid leukemic cell clone WEHI 3B (JCS) were investigated. The survival rate of mice receiving PCRJ treated JCS tumour cells was also increased. Using 1H-NMR, 13C-NMR, and GC/MS, two active components isolated from PCRJ were identified as nobiletin and tangeretin.2
Liver cancer
Dietary phytochemicals can inhibit the development of certain types of tumors. We here investigated the effects of nobiletin (Nob), garcinol (Gar), auraptene (Aur), beta-cryptoxanthin- and hesperidine-rich pulp (CHRP) and 1,1'-acetoxychavicol acetate (ACA) on hepatocarcinogenesis in a rat medium-term liver bioassay, and also examined their influence on cell proliferation, cell cycle kinetics, apoptosis and cell invasion of rat and human hepatocellular carcinoma (HCC) cells, MH1C1 and HepG2, respectively.3
Lung cancer
Furthermore, Nobiletin had overt inhibitory effect on the tumor growth in nude mice model was observed in vivo. Taken together, these results suggest that Nobiletin could induce p53-mediated cell cycle arrest and apoptosis via modulated the Bax:Bcl-2 protein ratio, is effective as a potent antitumor agent on lung tumors.4
Prostate cancer
A further experiment demonstrated that growth of androgen sensitive LNCaP and androgen insensitive DU145 and PC3 human prostate cancer cells, was suppressed by both nobiletin and to a lesser extent auraptene in a dose-dependent manner, with significant increase in apoptosis. In conclusion, these compounds, particularly nobiletin, may be valuable for prostate cancer prevention.5
Squamous Cell Carcinoma
Tangeretin and nobiletin markedly inhibited the proliferation of a squamous cell carcinoma (HTB 43) and a gliosarcoma (9L) cell line at 2-8 micrograms/ml concentrations. 6
Stomach cancer
Although the effective dose and administration route of nobiletin require further investigation, our study represents a potential successful linking of this compound with the treatment of gastric cancer.7

Quercetin

CancerAbstractReference
Breast cancer
There has been considerable evidence recently demonstrating the anti-tumour effects of flavonols. Quercetin, an ubiquitous bioactive flavonol, inhibits cells proliferation, induces cell cycle arrest and apoptosis in different cancer cell types. Taken together, these findings suggest that quercetin results in human breast cancer MDA-MB-231 cell death through mitochondrial- and caspase-3-dependent pathways.1
Cervical cancer
Quercetin showed a marked inhibitive effect on U14 growth, and its antitumor mechanism may be associated with inhibiting the angiogenesis and inducing apoptosis.2
Colon cancer
In conclusion, quercetin, but not rutin, at a high dose reduced colorectal carcinogenesis in AOM-treated rats, which was not reflected by changes in ACF-parameters. The lack of protection by rutin is probably due to its low bioavailability.3
Endometrial cancer
This study suggests a reduction in endometrial cancer risk with quercetin intake and with isoflavone intake in lean women.4
Esophageal cancer
The results of MTT assay showed that flavones (luteolin, apigenin, chrysin) and flavonols (quercetin, kaempferol, myricetin) were all able to induce cytotoxicity in OE33 cells in a dose- and time-dependent manner, and the cytotoxic potency of these compounds was in the order of quercetin > luteolin > chrysin > kaempferol > apigenin > myricetin. 5
Gliomas
Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin–induced apoptosis was markedly reduced by overexpression of survivin. In addition, upon treatment with quercetin, downregulation of survivin was also regulated by the Akt pathway. Taken together, the results of the present study suggest that quercetin sensitizes glioma cells to death-receptor–mediated apoptosis by suppression of inhibitor of the apoptosis protein survivin.6
Kidney cancer
These results suggest that the flavonoid quercetin may prevent renal cell cancer among male smokers. The possible risk associated with fish intake warrants further investigation before conclusions may be drawn.7
Laryngeal cancer
Quercetin could effectively inhibit the proliferation of Hep-2 cells and its mechanism is probably related to the apoptosis.8
Leukemia
It is concluded that the quercetin and kaempferol have significant anti-leukemia effect in vitro. Furthermore the apoptosis-inducing effect of quercetin is stronger than that of kaempferol, both of which induce apoptosis of HL-60 cells through depressing cell growth, arresting cell cycle and inhibiting expression of survivin.9
Liver cancer
Quercetin, a dietary flavonoid, has been shown to possess anticarcinogenic properties, but the precise molecular mechanisms of action are not thoroughly elucidated. The aim of this study was to investigate the regulatory effect of quercetin (50 microM) on two main transcription factors (NF-kappa B and AP-1) related to survival/proliferation pathways in a human hepatoma cell line (HepG2) over time. Quercetin induced a significant time-dependent inactivation of the NF-kappa B pathway consistent with a downregulation of the NF-kappa B binding activity (from 15 min onward).10
Lung cancer
Lung cancer was associated inversely with the consumption of epicatechin (in 10 mg per day increment: OR, 0.64; 95% CL, 0.46-0.88), catechin (4 mg per day increment: OR, 0.49; 95% CL, 0.35-0.70), quercetin (9 mg per day increment: OR, 0.65; 95% CL, 0.44-0.95), and kaempferol (2 mg per day increment: OR, 0.68; 95% CL, 0.51-0.90) among tobacco smokers.11
Melanoma
In this paper, the DNA protective free radical scavenging potential of quercetin (QU) and luteolin (LU) against H2O2 and their clastogenic effect alone and in combination with melphalan (MH) were investigated in human melanoma HMB-2 cells. Results are correlated to their structural arrangement and organization of the hydroxyl groups.12
Mouth cancer
In conclusion, our data support a view that quercetin initially induces a stress response, resulting in necrosis of these oral epithelial cells. Prolonged exposure of the surviving cells to quercetin causes apoptosis, presumably mediated by inhibition of TS protein.13
Ovarian cancer
It has been demonstrated that the flavonoid quercetin (3,3',4',5-7-pentahydroxyflavone) (Q) inhibits the growth of several cancer cell lines and that the antiproliferative activity of this substance is mediated by a so-called type II estrogen binding site (type II EBS). Since both rutin and hesperidin do not bind to type II EBS it can be hypothesized that Q synergizes with CDDP by acting through an interaction with these binding sites.14
Pancreatic cancer
Our studies aimed at evaluation of antiproliferative and pro-apoptotic effects of quercetin alone and in combinations with daunorubicin on cells of human pancreatic carcinoma lines. Our data demonstrated that quercetin exerted cytotoxic action on cells of the both neoplastic cell lines in concentration-dependent manner. In the case of EPP85-181RDB cell line, quercetin seemed to sensitize resistant cells to daunorubicin.15
Prostate cancer
Taken together, as shown by the issues of the current study, the manifold inhibitory effects of quercetin on PC-3 cells may introduce quercetin as an efficacious anticancer agent in order to be used in the future nutritional transcriptomic investigations and multi-target therapy to overcome the therapeutic impediments against prostate cancer.16
Squamous Cell Carcinoma
We examined the effects of flavone and two polyhydroxylated plant flavonoids (quercetin and fisetin), either singly or in combination with ascorbic acid, on the growth of a human squamous cell carcinoma cell line (HTB 43) in vitro. Fisetin and quercetin significantly impaired cell growth in the presence of ascorbic acid. 17
Stomach cancer
Cells were divided into the control group and the quercetin (Que)-treated group. Que significantly decreased the expression of VEGF-C and VEGFR-3 at 40 mumol/L compared with the control group after 48 h (P18

Rutin

CancerAbstractReference
Colon cancer
The dietary effect of monoglucosyl-rutin (M-R), a flavonoid, on azoxymethane (AOM)-induced colon carcinogenesis was investigated in two experiments with 5 week old, F344 male rats. At the termination of the experiment (40 weeks after the start), groups 2-5 had significantly smaller numbers of positive cells with anti-proliferating cell nuclea antigen (PCNA) antibody than group 1. Furthermore, group 5 treated with 500ppm M-R for 36 weeks demonstrated tendencies for decrease in the incidence and multiplicity of colon tumors. These data suggest that M-R has the potential to inhibit AOM-induced colon carcinogenesis.1
During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.2
Melanoma
Consequent to the inhibition of the lung tumor nodules, the life span of animals treated with polyphenols was also found to be increased. Curcumin (143.85%), catechin (80.81%) and rutin (63.59%) had maximal increase in life span. The results indicate a possible use of these compounds in arresting the metastatic growth of tumor cells.3

Tangeritin

CancerAbstractReference
Breast cancer
Tangeretin is a methoxyflavone from citrus fruits, which inhibits growth of human mammary cancer cells and cytolysis by natural killer cells. Attempting to unravel the flavonoid's action mechanism, the authors found that it inhibited extracellular-signal-regulated kinases 1/2 (ERK1/2) phosphorylation in a dose- and time-dependent way. In human T47D mammary cancer cells this inhibition was optimally observed after priming with estradiol. 1
Colon cancer
Tangeretin and nobiletin are citrus flavonoids that are among the most effective at inhibiting cancer cell growth in vitro and in vivo. The antiproliferative activity of tangeretin and nobiletin was investigated in human breast cancer cell lines MDA-MB-435 and MCF-7 and human colon cancer line HT-29. Thus, tangeretin and nobiletin could be effective cytostatic anticancer agents. Inhibition of proliferation of human cancers without inducing cell death may be advantageous in treating tumors as it would restrict proliferation in a manner less likely to induce cytotoxicity and death in normal, non-tumor tissues.2
Leukemia
Tangeretin showed no cytotoxicity against either HL-60 cells or mitogen-activated PBMCs even at high concentration (27 microM) as determined by a dye exclusion test. Moreover, the flavonoid was less effective on growth of human T-lymphocytic leukaemia MOLT-4 cells or on blastogenesis of PBMCs. These results suggest that tangeretin inhibits growth of HL-60 cells in vitro, partially through induction of apoptosis, without causing serious side-effects on immune cells.3
Melanoma
Tangeretin was the most effective of the flavonoids in inhibiting B16F10 and SK-MEL-1 cell growth, showing a clear dose-response curve after 72 h. These results suggest that the absence of the C2-C3 double bond on hydroxylated flavonoids results in a loss of effect on both the cell lines, while the higher activity of tangeretin compared with 7,3'-dimethylhesperetin suggests that the presence of at least three adjacent methoxyl groups confers a more potent antiproliferative effect.4
Squamous Cell Carcinoma
 We investigated the antiproliferative effect of two polyhydroxylated (quercetin and taxifolin) and two polymethoxylated (nobiletin and tangeretin) flavonoids against three cell lines in tissue culture. Tangeretin and nobiletin markedly inhibited the proliferation of a squamous cell carcinoma (HTB 43) and a gliosarcoma (9L) cell line at 2-8 micrograms/ml concentrations. 2

A number of different varieties of citrus has been used in the numerous studies of citrus peel extracts.  A list of the most commonly used varieties are as follows:

  • Mandarin orange (Citrus reticulata)
  • Satsuma Mandarin (Citrus unshiu)

The Chinese have been using Chenpi or chen pi (Chinese: 陈皮, pinyin: chénpí) as a traditional seasoning in Chinese cooking and traditional medicine.  Chen pi is a sun dried tangerine (mandarin).  Some Chen pi is made from the mandarin orange (Citrus reticulata ‘Blanco’) and bitter orange (C. aurantium).  11

Chen pi contains a high content of 5-demethylated polymethoxyflavones (5-OH PMFs).  12  Oral administration of 0.25 and 0.5% chenpi extract in food over 15 weeks markedly prevented HFD-induced obesity, hepatic steatosis, and diabetic symptoms.  13

The varieties of citrus that are good candidates for citrus peel powder are the following:

  • Bitter Orange  (Citrus aurantium)
  • Sweet Orange (Citrus sinensis L. Osbeck)
  • Mandarin (Chinese) Tangerine  (Citrus reticulata)
  • Satsuma Mandarin  (Citru unshiu)
  • Chinese Honey Orange (Ponkan)  (Citrus poonensis)
  • Yuzu (Citrus ichangensis × C. reticulata)
  • Grapefruit  (Citrus paradisi)
  • Meyer Lemon (Citrus × meyeri)

When consuming citrus peel from any of the above varieties, it is important to choose the organic variety only.  Citrus fruits can be heavily sprayed with pesticides which tend to concentrate on the outer peel.  The fruit should be washed prior to using the peel, whether raw (zest) or dried and ground into citrus peel powder. 

Raw citrus peel (zest) can be used in salads, yogurt, tea, added to smoothies, stews, vegetable dishes as well as added to fish as a garnish.  The dried and grounded citrus peel powder can be added to smoothies and soups.

Images of various citrus fruits used for citrus peel and citrus peel powder:

  • Bitter Orange (Citrus aurantium)

How to Make Pure Orange Peel Powder at Home

Cover Photo from Nan Products