ANTI-CARCINOGENIC POSSESSIONS OF CITRUS PEEL EXTRACT AND

FLAVONOIDS: A REVIEW
Author: Bakhtawar Shafique

Mentor: Dr. Shahid Mahmood

Institute of Food Science and Nutrition (IFSN) University of Sargodha

INTRODUCTION FLOW CHART OF FLAVONOID NOBILETIN

ACTION ON CANCER CELLS
 Lethal disease cancer is usually treated with synthesized drugs
and medications associated with numerous side effects
• Low blood counts
• Hair loss
FLAVONOID
• Peripheral neuropathy Induction of NOBILETIN Inhibition
• Arthralgias and myalgias apoptosis in of NO
• Nausea and vomiting TMK-1 cells generation
• Diarrhea
• Mouth sores Reduced the Downregulation
• Hypersensitivity reaction ACF of proMMPs-1
• Blood clot incidence and -3
Induction of
Taxol et al.,(2019) Inhibition of
G1cell cycle
 Citrus peel enriched with polymethoxylated flavones, arrest
O2ˉ2ˉ generation
flavonoids and bioactive substances associated to treat malignant Suppress Upregulation of
tumours and neoplasms. colon TIMP-1
Suzawa et al., (2014) carcinogenesis production
Combined
Suppression
effect of
of PGE22
nobiletin
production
with CDDP Inhibits iNOS Suppression of
and COX-2 COX-2
expression production

Table 1: COMPOSITION OF PMF AND

Anticarcinogenesis
HYDROXYLATED PMF IN ORANGE PEEL
EXTRACT DIETARY ADMINISTRATION OF DIOSMIN
OH-PMFs and PMFs Concentration AND HESPERIDIN
(mg/g OH- PMFs) Flavonoids Doses fed in F344 rats Duration
5Hydroxy3,6,7,8,3´,4 254.78 ± 4.95 Initiation Post-initiation
treatment treatment
´hexamethoxy flavone
Diosmin 1000 ppm 1000 ppm 5 weeks
5-Hydroxy-6,7,8,3´,4´- 396.42 ± 4.62
pentamethoxyflavone Hesperidin 900 ppm 100 ppm 28 weeks
Doses fed in male wistar rats
5-hydroxy-3,6,7,3´,4´ 7.08 ± 0.11
pentamethoxyflavone Initiation Post-initiation
treatment treatment
5-hydroxy-6,7,8,4´- 74.96 ± 0.16
Diosmin 1000 ppm 900 ppm 13 weeks
tetramethoxyflavone
Hesperidin 1000 ppm 100 ppm 7 weeks
5-hydroxy-6,7,4´- 115.52 ± 2.35
Result showed:
trimethoxyflavone • 78 and 58% reduction due to diosmin
5-hydroxy-6,7,3´,4´- 44.5 ± 0.08 • 70 and 50% reduction by hesperidin
• Combination regimen caused 70 and 30% reduction in carcinoma
tetramethoxyflavone cells Tanaka et al., (1997)
Nobiletin 10.41 ± 0.14 GOLD LOTION
Heptamethoxyflavone 55.04 ± 0.46  Gold lotion (GL) is a formulated product from citrus peel extract
Tangeretin 20.34 ± 0.62 result showed beneficial aspects:
• Treat prostate, skin and colon cancer in mice
Lai et al., (2011) Molecular Nutrition & Food Research • Inhibited skin inflammation-associated tumourigenesis
• Reduced tumor incidence, tumor weight and tumor multiplicity of
papillomas
• Identifies opportunities for subsequent human clinical trials
BIOACTIVE CITRUS PEEL FLAVONOIDS Lai et al., (2013)
FORMULATION OF GOLD LOTION
• Flavonoids are the polyphenolic molecules containing 15
carbon atoms and appear as two benzene rings that are linked CITRUS MATERIALS AND RESULTS
together by a three-carbon chain VARIETIES METHODS
 Regarded as
navel oranges, • Measurement of • Inhibitory effects of
• Anti-oxidant citrus hassaku, hyperplasia GL on TPA-induced
• Anti-viral citrus limon, • Western blot analysis iNOS, COX-2
• Anti-carcinogenic citrus • Reverse transcription expression and
• Anti-tumour natsudaidai, polymerase (RT-PCR) epidermal hyperplasia
• Anti-inflammatory citrus miyauchi chain reaction in mouse skin
Sweet oranges • Two-stage skin • Inhibition of tumor
• Anti-proliferative
(Citrus sinensis) carcinogenesis model promotion, tumor size
Sally Robertson et al.,(2019) Mandarin oranges • Experiments in mouse and the expression of
 Major citrus peel flavonoids preventing cancer are: (Citrus reticulate) colon cancer and angiogenic
• Nobiletin prostate cancer molecule by GL (two-
• Quercetin • In vivo tumor xenograft stage skin
• Tangeretin study carcinogenesis model)
• Western blot analysis • Colon cancer and
• Diosmin
• HPLC (high prostate cancer
• Hesperidin performance liquid inhibition by GL
• Apigenin chromatography) system
• Luteolin • Quantification of (PMFs)
Flavonoids and Human Cancers. Journal Of Food And
Nutrition Research (2014)
RELATIONSHIP OF CITRUS PEEL CONCLUSION
FLAVONOIDS TO HUMAN CANCERS
This review summarizes the results of currently available data
FLAVONOID IMPACT ON HUMAN CANCERS regarding
S • in vivo and in vitro analysis of anti-cancer, anti-inflammatory and
Tangeretin • IC50 value range between 0.062 and 0.173 µM anti-proliferative activities of Citrus peel flavonoid
suppressed the growth of HL-60 cells in vitro • Have multiple active molecular components including flavonoids
Pan et al., (2002) • Provide opportunities for human clinical trials to deal with
• Exhibit anti-proliferative activity towards a preventive and therapeutic effects
human squamous cell carcinoma cell line • Formulation of numerous new product to deal with the fatal disease
• Inhibit tumor invasion and metastasis like cancer
Hirano et al., (1995)
REFERENCES
Quercetin, • showed high anti-tumorigenic potential and 1. Cancer, C. (2019). Taxol - Chemotherapy Drugs - Chemocare.
kaempferol, anti proliferative activities 2. Suzawa, M., L., Guo, H., Pan, M. Ho, T., C. & Li, S. 2014. In vivo anti-carcinogenic property of a
formulated citrus peel extract. Functional Foods in Health and Disease, 4(3), 120-129
luteolin Knowles et al., (2000) 3. Sally Robertson, B. (2019). What are Flavonoids?.
• suppress human prostate tumor proliferation 4. Ke, Z., pan, Y., Xu, X., Nie, C., & Zhou, Z. (2015). <i>Citrus</i> Flavonoids and Human
Cancers. Journal Of Food And Nutrition Research, 3(5), 341-351.
Quercetin and • Inhibit lung colonization of B16-BL6 5. Kohno, H., Yoshitani, I., S. Y., Tsukio, A., Murakami, K., Koshimizu, M., Yano,... & Tanaka, T.2001,
Dietary administration of citrus nobiletin inhibits azoxymethane-induced colonic aberrant crypt
apigenin cells, melanoma growth and metastatic foci in rats. Life sciences, 69(8), 901-913.
potential 6. Lin, N., T., Sato, Y., Takayama, Y., Mimaki, Y., Sashida, M., Yano, & A. Ito, 2003, Novel anti-
inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts
• Inhibit the growth of B16-BL6 melanoma cells and mouse macrophages. Biochemical pharmacology, 65(12), 2065-2071.
in vitro and in vivo in a concentration 7. Pan, M. H., J., Chen, W. Y., Lin-Shiau, S. T., Ho, C. & J. K. Lin, 2002, Tangeretin induces cell-cycle G1
dependent manner Caltagirone et al.,(2000) arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk
inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis, 23(10), 1677-1684.
8. Hirano, T., K., Abe, M., Gotoh, & K. Oka, 1995 Citrus flavone tangeretin inhibits leukaemic HL-60
Quercetin • Inhibited metastases in animal studies of cell growth partially through induction of apoptosis with less cytotoxicity on normal
lymphocytes. British journal of cancer, 72(6), 1380
chalcon and prostate cancer and melanoma 9. Tanaka, T., H., Makita, K., Kawabata, H., Mori, M., Kakumoto, H. Satoh, K., & Ogawa, 1997.
modified citrus • Exhibit antitumor properties and significant Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring
pectin (MCP) reduction in tumor size Hayashi et al., (2000) flavonoids, diosmin and hesperid. Carcinogenesis, 18(5), 957-965.
10. Lai, C. S., S., Li, Y., Miyauchi, M., Suzawa, C. T., Ho, & M. H. Pan, 2013, Potent anti-cancer effects
of citrus peel flavonoids in human prostate xenograft tumors. Food & function, 4(6): 944-949.