Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention
Abstract
1. Introduction
2. Research Methodology
3. Nobiletin and Its Derivatives
4. Pathogenesis of Colorectal Cancer
5. Chemopreventive Effects of Nobiletin, 5-DMN and NOB-Metabolites
5.1. Cell Cycle Arrest
5.1.1. Action of NOB and Its Metabolites Inducing Cell Arrest
5.1.2. Action of 5-DMN Inducing Cell Cycle Arrest
5.2. Programmed Cell Death
Action of NOB and Metabolites Inducing Programmed Cell Death
5.3. Anti-Inflammation
Anti-Inflammation Effect of NOB and Its Metabolites
5.4. Anti-Angiogenesis
Anti-Angiogenesis Effect of NOB
6. Pharmacokinetics, Bioavailability and Delivery Systems of NOB
7. Toxicity
8. Commercial Uses
9. Future Directions
10. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compounds | Activities | Cell lines | Treatment/Assay (Treatment Duration) | Assays/Results/Mechanisms | References |
---|---|---|---|---|---|
NOB | Anti-proliferative | HT-29 | H-thymidine uptake assay | - IC50 of NOB = 4.7 μM | [70] |
- IC90 of NOB = 13.9 μM | |||||
5-DMN | - IC50 of 5-DMN = 8.5 μM | ||||
- IC90 of 5-DMN = 171 μM | |||||
NOB | Cytotoxicity | COLO320, SW480 and Caco-2 | MTS viability assay (48 h) | - IC50 for COLO320 = 40.4 ± 9.1 μM | [79] |
- IC50 for SW480 = 245 ± 9.1 μΜ | |||||
- IC50 for Caco-2 = 305.6 ± 41.9 μΜ | |||||
Apoptosis-inducing | Apoptosis assays—DNA fragmentation | - DNA ladder pattern | |||
200 μΜ—2-fold increase DNA fragmentation in COLO320 | |||||
- gel electrophoresis (48 h) | |||||
Anti-proliferative | BrdU labelling index | - 34.7 ± 4.7% BrdU-binding cells at 100 μΜ | |||
- 44.4 ± 6.4% BrdU-binding cells at 40 μΜ | |||||
NOB | Anti-metastasis | HT-29 | ELISA | [77] | |
- proMMP-7 expression | - At 100 μM, no detection of proMMP-7 in media, ~280 pg/mL proMMP-7 in media | ||||
qPCR and Western blot | - >25 μM, reduced RNA and protein (both intracellular and supernatant) expression of proMMP-7 | ||||
AP-1 binding activity | - Inhibited binding activity of AP-1 (transcription factor for MMP-7 gene) | ||||
NOB | Anti-proliferative | HT-29 | Cell counting assay | - IC50 of NOB ≈ 50 μM | [14] |
- Inhibited cell proliferation in a time- and dose-dependent manner | |||||
Cell cycle arrest | |||||
Cell cycle analysis | - Induced G1 phase cell cycle arrest (60 and 200 μM) | ||||
- Propidium iodide staining | |||||
Apoptosis-inducing | Apoptosis assay | - No significant apoptosis detected at 60 and 100 μM | |||
Resumption of proliferation | - Resumed proliferation within 24 h of removal of NOB and achieve the same stage of growth as compared to control after four days of removal of NOB | ||||
NOB 5-DMN | Cytotoxicity | HCT116, HT-29 | MTT viability assay (48 h) | - IC50 of NOB on HCT116 = 37 μM | [63] |
- IC50 of 5-DMN on HCT116 = 8.7 μM | |||||
- IC50 of NOB on HT-29 = 46.2 μM | |||||
- IC50 of 5-DMN on HT-29 = 22 μM | |||||
Cell cycle arrest | Cell cycle analysis - Propidium iodide staining (24 h) Western blot | - At 8 μM, 5-DMN induced G2/M phase arrest in HCT116 | |||
- At 36 μM, 5-DMN induced G2/M phase arrest in HT-29 | |||||
- At 16 μM, NOB reduced CDK-2 expression | |||||
- At 4 μM and 8 μM, 5-DMN increased p21 and Rb, while decreased CDK-2 and p-Rb. | |||||
Apoptosis-inducing | Apoptosis assay | - At 8 μM, 5-DMN increased early apoptosis by 2.2-fold in HCT116 | |||
Annexin-V/PI (48 h) | - At 36 μM, 5-DMN increased early apoptosis by ~2-fold in HT-29 | ||||
Western blot | - At 16 μM, NOB did not increase apoptotic cell population in HCT116/HT-29 | ||||
- At 4 μM and 8 μM, 5-DMN increased expressions of cleaved caspase 8, cleaved caspase 3 and cleaved PARP. | |||||
5-DMN | Apoptosis-inducing | HCT116 (p53 +/+) and HCT116 (p53 −/−); HCT116 (Bax +/−) and HCT116 (Bax −/−); HCT116 (p21 −/−) | Apoptosis assay Annexin-V/PI | - At 15 μM, 5-DMN increased late apoptotic/necrotic cell in HCT116 (p53 −/−) > HCT115 (p53 +/+), suggesting the apoptotic inducing action is independent of p53 | [80] |
- At 15 μM, 5-DMN increased early apoptotic cell in HCT116 (Bax +/−), but not in HCT116 (Bax −/−) | |||||
Cell cycle arrest | Cell cycle analysis - Propidium iodide staining | - At 15 μM, 5-DMN arrested cells at G2/M and G0/G1 phases in HCT116 (p53 +/+) cells, but only caused G2/M phase arrest in HCT116 (p53 −/−) cells | |||
- G0/G1 is p53 dependent and G2/M is p53-independent | |||||
NOB; 3′-DMN; 4′-DMN; 3′,4′-DMN | Cytotoxicity | HCT116, HT-29 | MTT viability assay | - At 2.03 μM and 3.28 μM, NOB and 3′-DMN, respectively showed no significant cytotoxicity against HCT116 and HT-29 | [54] |
- At 24.13 μM, 4′-DMN inhibited growth of HCT-116 by 45% and HT-29 by 33% | |||||
- At 12.03 μM, 3’,4’-DMN inhibited growth of HCT116 by 30% and HT-29 by 9% | |||||
- combination of all three NOB-metabolites inhibited growth of HCT116 by 64% and HT-29 by 62% (no significant difference to three NOB-metabolites + NOB) | |||||
Cell cycle arrest | Cell cycle analysis - Propidium iodide staining (24 h) | - NOB (40 μM) arrested cells at G0/G1 phase in both HCT-116 and HT-29 | |||
- 3′-DMN (40 μM) arrested cells at both S phase and G2/M phase in HCT-116; while arrested cells at both G0/G1 and G2/M phase in HT-29 | |||||
- 4′-DMN (40 μM) induced a stronger effect than NOB in arresting cells at G0/G1 phase in HCT-116 and HT-29 | |||||
- 3′,4′-DMN (20 μM) arrested cells at both S phase and G2/M phase in HCT-116; while arrested cells at both G0/G1 and G2/M phase in HT-29 | |||||
Apoptosis inducing | Western blot | - NOB and all three NOB-metabolites cause profound increase in expression of p21Cip1/Waf1 | |||
Annexin-V/PI (48 h) | - NOB (40 μM) increased early apoptotic cell population by 3.3-fold, increased late apoptotic cell population by 4.2-fold in HCT116 | ||||
- 3′-DMN (40 μM) increased early apoptotic cell population by 5.0-fold, increased late apoptotic cell population by 3.5-fold in HCT116 | |||||
- 4′-DMN (40 μM) increased early apoptotic cell population by 4.9-fold, increased late apoptotic cell population by 7.1-fold in HCT116 | |||||
- 3′,4′-DMN (20 μM) increased early apoptotic cell population by 7.6-fold, increase late apoptotic cell population by 4.5-fold in HCT116 | |||||
-3′-DMN (40 μM) and 4’-DMN (40 μM) did not cause significant apoptosis in HT-29 | |||||
- 3′,4′-DMN (20 μM) exhibits stronger apoptosis effect than NOB (40 μM) in HT-29 | |||||
Western blot | - NOB (40 μM) only increased activation of caspase-9 and did not affect caspase-3 or PARP levels in HCT116 | ||||
- NOB-metabolites increased activation of caspase-3, caspase-9 and other downstream proteins like PARP in HCT116 | |||||
NOB-Met (2.03 μM NOB: 3.28 μM 3′-DMN: 24.13 μM 4′-DMN: 12.03 μM 3′,4′-DMN | Anti-inflammatory | RAW264.7 | Western Blot | - At 0.5× concentration of NOB-Met, supressed LPS-induced iNOS expression by 56.4% | [76] |
- At 1× and 2× concentration of NOB-Met, completely abrogated LPS-induced iNOS expression | |||||
- At ×0.5, increased expression of NQO1 by 21% as compared to LPS-treated cells | |||||
- At ×1, increased expression of HO-1 by 10%, increased expression of NQO1 by 34% as compared to LPS-treated cells | |||||
- At ×2, increased expression of HO-1 by 37%, increased expression of NQO1 by 50% as compared to LPS-treated cells | |||||
- Induced translocation of Nrf2 | |||||
Cell cycle arrest | HCT116 | Cell cycle analysis - Propidium iodide staining Western blot | - At 1×, induced G0/G1 phase arrest; while at 2×, induced G0/G1 and G2/M phases arrest | ||
- Reduced expressions of CDK-2, CDK-4, CDK-6 and cyclin D, while increased expressions of p53 and p27 | |||||
NOB, 5-DMN | Cytotoxicity | HCT116, HT-29, COLO205 | MTT viability assay | - At 40 μM, NOB significantly reduced viability of HCT116, HT-29 and COLO205 by ~20–30% | [49] |
- At >5 μM, 5-DMN significantly reduced viability of HCT116, HT-29 and COLO205 | |||||
Apoptosis inducing | Cell cycle analysis - SubG1 quantification Western | - At 20 μM, 5-DMN increased apoptosis ratio by ~26%, while no increased in subG1 population in NOB-treated COLO205 | |||
- At 10 and 20 μM, significantly increased expression of cleaved PARP in COLO205 | |||||
NOB | Anti-inflammatory | Human synovial fibroblast, mouse macrophage J774A.1 | ELISA | - At >4 μM, NOB inhibited PGE2 induced by IL-1α in human synovial fibroblast | [81] |
Western blot and qPCR | - At >16 μM, NOB reduced mRNA of COX-2 induced by IL-1α in human synovial fibroblast | ||||
- At 64 μM, NOB inhibited COX-2 protein expression induced by IL-1α in human synovial fibroblast | |||||
qPCR | - At 32 μM, NOB reduced mRNA of IL-1α, IL-1β, IL-6, TNF-α induced by LPS in J774A.1 | ||||
Western blot | - At >16 μM, NOB reduced proMMP-1 and proMMP-3 induced by IL-1α in human synovial fibroblast | ||||
- At >16 μM, NOB enhanced TIMP-1 expression in response to IL-1α in human synovial fibroblast | |||||
NOB | Anti-inflammatory | Mouse adipocyte 3T3-L1 | ELISA | - At 50 and 100 μM, NOB suppressed MCP-1 secretion induced by TNF-α IN 3T3-L1 adipocytes | [82] |
Western blot | - At 50 and 100 μM, NOB reduced ERK phosphorylation in 3T3-L1 adipocytes treated with TNF-α |
Animal Models | Treatment/Dosage | Mechanisms | Detailed Results | References |
---|---|---|---|---|
Colitis-associated colon carcinogenesis model
| AIN93G diet containing 0.05% wt NOB (20 weeks) | Cell cycle arrest | Protein expression in colonic mucosa by Western blot - Reduced levels of CDK-2, CDK-4, CDK-6, cyclin D and cyclin E - Increased levels of p21, p27 and p53 | [76] |
Anti-inflammatory effects | Immunohistochemical analysis - Reduced expression of iNOS reduced by 35% when compared to the positive control Protein expression in colonic mucosa by Western blot - Increased level of HO-1 - Increased level of NQO1 - Induced translocation of level of Nrf2 transcription factor (Nuclear fraction < Cytoplasmic fraction) | |||
Colitis-associated colon carcinogenesis model
| AIN93G diet containing 0.05% wt NOB (20 weeks) | Inhibit AOM/DSS-induced colon carcinogenesis | - Prevented shortening of colon length, reduced the increased colon weight/length ratio - Reduced tumor incidence by 40% and tumor multiplicity by 71% - Maintained histological characteristic of normal mucosa | [54] |
Anti-proliferative effect | - Reduced PCNA-positive colonocytes by 69% in mucosal crypts | |||
Apoptosis-inducing effect | - Increased cleaved caspase-3 positive cells by 2.3-fold in colonic tumor | |||
Anti-inflammatory effects | - Reduced levels of proinflammatory cytokines - ELISA showed reduction of TNF-α by 51%, IL-1ß by 92% and IL-6 by 69% compared - qRT-PCR analysis showed reduction of TNF-α by 65%, IL-1ß by 69% and IL-6 by 45% | |||
Colon carcinogenesis model
| Diet containing 100 ppm NOB (0.1% wt) (10 weeks) | Inhibit AOM induced colon carcinogenesis | - Reduced frequency of preneoplastic lesions (colonic aberrant crypt foci (ACF) and β-catenin-accumulated crypts (BCAC)) - Reduced incidence of ACF by 68-91% and BCAC by 64–71% - Reduced PCNA-labeling index in ACF by 21% and BCAC by 19% | [83] |
Colon carcinogenesis model
| Diet containing 100 ppm NOB (0.1% wt) (for 17 weeks) | Inhibit AOM/DSS-induced colon carcinogenesis | - Suppressed incidence of neoplasms (adenoma and adenocarcinoma), lowered multiplicity of tumor | [84] |
Inhibit leptin-induced colon carcinogenesis | ||||
- Suppressed serum levels of leptin by 75–84% | ||||
Colon carcinogenesis model
| Diet containing NOB (0.01% wt and 0.05% wt) (34 weeks) | Inhibit AOM induced colon carcinogenesis | - Reduced incidence and multiplicity of colonic adenocarcinoma | [74] |
Anti-proliferative effect | ||||
- Increased apoptosis index of adenocarcinoma | ||||
Anti-inflammatory effect | ||||
- Reduced level of PGE2 in colonic adenocarcinoma and surrounding mucosa | ||||
Colon carcinogenesis model
| Diet containing NOB (0.01% wt and 0.05% wt) (5 weeks) | Inhibit AOM-induced colon carcinogenesis | - Reduced the frequency of colonic aberrant crypt foci formation - Reduced number of ACF in proximal, middle and distal colon | [41] |
Anti-proliferative effect | ||||
- Reduced MIB-5 labeling index of ACF but not of normal colonic crypts | ||||
Anti-inflammatory effect | ||||
- Reduced level of PGE2 in colonic mucosa | ||||
Colon carcinogenesis model
| Diet containing NOB (0.05% wt.) (50 weeks) | Inhibit PhIP-induced ACF in transverse colon | - Reduced the total colonic ACF indices in transverse colon | [75] |
Colorectal cancer xenograft mouse model
| NOB 100 mg/kg i.p. daily for 3 weeks 5-DMN 50 mg/kg and 100 mg/kg i.p. daily for 3 weeks | Anti-tumor effect | - NOB reduced tumor size and weight but not significant as compared to control - 5-DMN reduced tumor size and weight significantly as compared to control | [49] |
Autophagy induction | - 5-DMN increased LC3 expression | |||
Anti-inflammatory effect | ||||
- 5-DMN increased p53 expression - 5-DMN reduced COX-2 expression | ||||
Anti-angiogenesis | ||||
- 5-DMN reduced VEGF expression |
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Goh, J.X.H.; Tan, L.T.-H.; Goh, J.K.; Chan, K.G.; Pusparajah, P.; Lee, L.-H.; Goh, B.-H. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers 2019, 11, 867. https://doi.org/10.3390/cancers11060867
Goh JXH, Tan LT-H, Goh JK, Chan KG, Pusparajah P, Lee L-H, Goh B-H. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers. 2019; 11(6):867. https://doi.org/10.3390/cancers11060867
Chicago/Turabian StyleGoh, Joanna Xuan Hui, Loh Teng-Hern Tan, Joo Kheng Goh, Kok Gan Chan, Priyia Pusparajah, Learn-Han Lee, and Bey-Hing Goh. 2019. "Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention" Cancers 11, no. 6: 867. https://doi.org/10.3390/cancers11060867
APA StyleGoh, J. X. H., Tan, L. T.-H., Goh, J. K., Chan, K. G., Pusparajah, P., Lee, L.-H., & Goh, B.-H. (2019). Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers, 11(6), 867. https://doi.org/10.3390/cancers11060867