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Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents

  • Meiyanto, Edy (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Hermawan, Adam (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Anindyajati, Anindyajati (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada)
  • Published : 2012.02.29

Abstract

Targeted therapy has been a very promising strategy of drug development research. Many molecular mechanims of diseases have been known to be regulated by abundance of proteins, such as receptors and hormones. Chemoprevention for treatment and prevention of diseases are continuously developed. Pre-clinical and clinical studies in chemoprevention field yielded many valuable data in preventing the onset of disease and suppressing the progress of their growth, making chemoprevention a challenging and a very rational strategy in future researches. Natural products being rich of flavonoids are those fruits belong to the genus citrus. Ethanolic extract of Citrus reticulata and Citrus aurantiifolia peels showed anticarcinogenic, antiproliferative, co-chemotherapeutic and estrogenic effects. Several examples of citrus flavonoids that are potential as chemotherapeutic agents are tangeretin, nobiletin, hesperetin, hesperidin, naringenin, and naringin. Those flavonoids have been shown to possess inhibition activity on certain cancer cells' growth through various mechanisms. Moreover, citrus flavonoids also perform promising effect in combination with several chemotherapeutic agents against the growth of cancer cells. Some mechanisms involved in those activities are through cell cycle modulation, antiangiogenic effect, and apoptosis induction.Previous studies showed that tangeretin suppressed the growth of T47D breast cancer cells by inhibiting ERK phosphorylation. While in combination with tamoxifen, doxorubicin, and 5-FU, respectively, it was proven to be synergist on several cancer cells. Hesperidin and naringenin increased cytotoxicitity of doxorubicin on MCF-7 cells and HeLa cells. Besides, citrus flavonoids also performed estrogenic effect in vivo. One example is hesperidin having the ability to decrease the concentration of serum and hepatic lipid and reduce osteoporosis of ovariectomized rats. Those studies showed the great potential of citrus fruits as natural product to be developed as not only the source of co-chemotherapeutic agents, but also phyto-estrogens. Therefore, further study needs to be conducted to explore the potential of citrus fruits in overcoming cancer.

Keywords

Natural products;targeted therapy;cancer;citrus flavonoids;co-chemotherapy;chemoprevention

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  2. Anticancer Activity of Acacia nilotica (L.) Wild. Ex. Delile Subsp. indica Against Dalton's Ascitic Lymphoma Induced Solid and Ascitic Tumor Model vol.13, pp.8, 2012, https://doi.org/10.7314/APJCP.2012.13.8.3989
  3. Flavonoides como agentes quimiopreventivos y terapéuticos contra el cáncer de pulmón vol.16, pp.4, 2012, https://doi.org/10.1016/S2173-1292(12)70089-3
  4. Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5-fluorouracil vol.4, pp.2, 2013, https://doi.org/10.1038/cddis.2013.26
  5. Fisetin Inhibits Migration and Invasion of Human Cervical Cancer Cells by Down-Regulating Urokinase Plasminogen Activator Expression through Suppressing the p38 MAPK-Dependent NF-κB Signaling Pathway vol.8, pp.8, 2013, https://doi.org/10.1371/journal.pone.0071983
  6. and MDCK-derived cysts in a TRPP2 (polycystin-2)-dependent manner vol.171, pp.10, 2014, https://doi.org/10.1111/bph.12443
  7. Design, synthesis and experimental validation of novel potential chemopreventive agents using random forest and support vector machine binary classifiers vol.28, pp.6, 2014, https://doi.org/10.1007/s10822-014-9748-9
  8. Licochalcone A inhibits the migration and invasion of human lung cancer cells via inactivation of the Akt signaling pathway with downregulation of MMP-1/-3 expression vol.35, pp.12, 2014, https://doi.org/10.1007/s13277-014-2519-3
  9. Hesperidin protects testicular and spermatological damages induced by cisplatin in rats vol.47, pp.7, 2014, https://doi.org/10.1111/and.12332
  10. Analysis of Biologically Active Oxyprenylated Ferulic Acid Derivatives in Citrus Fruits vol.69, pp.3, 2014, https://doi.org/10.1007/s11130-014-0427-8
  11. Pro-Apoptotic Effects of the Novel Tangeretin Derivate 5-Acetyl-6,7,8,4′-Tetramethylnortangeretin on MCF-7 Breast Cancer Cells vol.70, pp.2, 2014, https://doi.org/10.1007/s12013-014-0049-7
  12. vol.80, pp.3, 2014, https://doi.org/10.1111/tpj.12637
  13. Licochalcone A Suppresses Migration and Invasion of Human Hepatocellular Carcinoma Cells through Downregulation of MKK4/JNK via NF-κB Mediated Urokinase Plasminogen Activator Expression vol.9, pp.1, 2014, https://doi.org/10.1371/journal.pone.0086537
  14. Naringenin modulates skeletal muscle differentiation via estrogen receptor α and β signal pathway regulation vol.9, pp.5, 2014, https://doi.org/10.1007/s12263-014-0425-3
  15. inhibits cyclophosphamide-induced immunosuppression and urotoxicity by modulating cytokines in mice vol.12, pp.2, 2015, https://doi.org/10.3109/1547691X.2014.914988
  16. Autophagy-associated Targeting Pathways of Natural Products during Cancer Treatment vol.15, pp.24, 2015, https://doi.org/10.7314/APJCP.2014.15.24.10557
  17. Multi-Target Cytotoxic Actions of Flavonoids in Blood Cancer Cells vol.16, pp.12, 2015, https://doi.org/10.7314/APJCP.2015.16.12.4843
  18. Inhibitory Aromatase Effects of Flavonoids from Ginkgo Biloba Extracts on Estrogen Biosynthesis vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6317
  19. Chemopreventive Actions of Blond and Red-Fleshed Sweet Orange Juice on the Loucy Leukemia Cell Line vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6491
  20. CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6783
  21. Anticancer Effect of Citrus Fruit Prepared by Gamma Irradiation of Budsticks vol.25, pp.9, 2015, https://doi.org/10.5352/JLS.2015.25.9.1051
  22. Simultaneous extraction and biotransformation process to obtain high bioactivity phenolic compounds from brazilian citrus residues vol.31, pp.5, 2015, https://doi.org/10.1002/btpr.2126
  23. Tangeretin enhances radiosensitivity and inhibits the radiation-induced epithelial-mesenchymal transition of gastric cancer cells vol.34, pp.1, 2015, https://doi.org/10.3892/or.2015.3982
  24. Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin vol.36, pp.12, 2015, https://doi.org/10.1007/s13277-015-3655-0
  25. Fisetin suppresses ADAM9 expression and inhibits invasion of glioma cancer cells through increased phosphorylation of ERK1/2 vol.36, pp.5, 2015, https://doi.org/10.1007/s13277-014-2975-9
  26. Current status and prospects of citrus genomics vol.42, pp.4, 2015, https://doi.org/10.5010/JPB.2015.42.4.326
  27. Targeting Cancer Stem Cells in Breast Cancer: Potential Anticancer Properties of 6-Shogaol and Pterostilbene vol.63, pp.9, 2015, https://doi.org/10.1021/acs.jafc.5b00002
  28. Chemopreventive and Therapeutic Potential of “Naringenin,” a Flavanone Present in Citrus Fruits vol.67, pp.1, 2015, https://doi.org/10.1080/01635581.2015.976320
  29. Muscadine Grape Skin Extract Induces an Unfolded Protein Response-Mediated Autophagy in Prostate Cancer Cells: A TMT-Based Quantitative Proteomic Analysis vol.11, pp.10, 2016, https://doi.org/10.1371/journal.pone.0164115
  30. Methoxylated flavones: occurrence, importance, biosynthesis vol.15, pp.3, 2016, https://doi.org/10.1007/s11101-015-9426-0
  31. A microalga, Euglena tuba induces apoptosis and suppresses metastasis in human lung and breast carcinoma cells through ROS-mediated regulation of MAPKs vol.16, pp.1, 2016, https://doi.org/10.1186/s12935-016-0330-5
  32. Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways vol.37, pp.1, 2016, https://doi.org/10.1007/s13277-015-3774-7
  33. Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway vol.37, pp.8, 2016, https://doi.org/10.1007/s13277-016-5013-2
  34. Rapid isolation, reliable characterization, and water solubility improvement of polymethoxyflavones from cold-pressed mandarin essential oil vol.39, pp.11, 2016, https://doi.org/10.1002/jssc.201501366
  35. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells vol.5, pp.1, 2016, https://doi.org/10.1038/srep18789
  36. Korean Byungkyul - Citrus platymamma Hort.et Tanaka flavonoids induces cell cycle arrest and apoptosis, regulating MMP protein expression in Hep3B hepatocellular carcinoma cells vol.50, pp.2, 2016, https://doi.org/10.3892/ijo.2016.3816
  37. Quantification of Flavonoids in Brazilian Orange Peels and Industrial Orange Juice Processing Wastes vol.08, pp.07, 2017, https://doi.org/10.4236/as.2017.87048
  38. Flavonoids, Thyroid Iodide Uptake and Thyroid Cancer—A Review vol.18, pp.6, 2017, https://doi.org/10.3390/ijms18061247
  39. Amelioration of Benzo[a]pyrene-induced oxidative stress and pulmonary toxicity by Naringenin in Wistar rats: A plausible role of COX-2 and NF-κB vol.36, pp.4, 2017, https://doi.org/10.1177/0960327116650009
  40. Estrogenic Potentials of Traditional Chinese Medicine vol.45, pp.07, 2017, https://doi.org/10.1142/S0192415X17500756
  41. Naringenin Impairs Two-Pore Channel 2 Activity And Inhibits VEGF-Induced Angiogenesis vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-04974-1
  42. Consumption of fruits, vegetables, and risk of hematological malignancies: a systematic review and meta-analysis of prospective studies vol.59, pp.2, 2018, https://doi.org/10.1080/10428194.2017.1339873
  43. Intake of dietary flavonoids and risk of epithelial ovarian cancer vol.100, pp.5, 2014, https://doi.org/10.3945/ajcn.114.088708
  44. Cytotoxic, genotoxic and apoptotic effects of naringenin-oxime relative to naringenin on normal and cancer cell lines vol.6, pp.10, 2016, https://doi.org/10.1016/j.apjtb.2016.08.004
  45. From folk medicine to functional food: a review on the bioactive components and pharmacological properties of citrus peels vol.18, pp.1, 2018, https://doi.org/10.1007/s13596-017-0292-8
  46. Suppressive effect of nobiletin and epicatechin gallate on fructose uptake in human intestinal epithelial Caco-2 cells vol.82, pp.4, 2018, https://doi.org/10.1080/09168451.2017.1387515
  47. Response of Myeloid Leukemia Cells to Luteolin is Modulated by Differentially Expressed Pituitary Tumor-Transforming Gene 1 (PTTG1) Oncoprotein vol.19, pp.4, 2018, https://doi.org/10.3390/ijms19041173
  48. Nobiletin suppresses cell viability through AKT Pathways in PC-3 and DU-145 prostate cancer cells vol.15, pp.1, 2014, https://doi.org/10.1186/2050-6511-15-59
  49. Metastatik Prostat Kanserinde Nobiletinin Sitotoksik ve Apoptotik Etkisinin Belirlenmesi vol.8, pp.4, 2018, https://doi.org/10.31832/smj.485666
  50. Safety Evaluation of a New Traditional Chinese Medical Formula, Ciji-Hua’ai-Baosheng II Formula, in Adult Rodent Models vol.2019, pp.1741-4288, 2019, https://doi.org/10.1155/2019/3659890