MERYEM AKPOLAT FERAH, Topçu Yeter TARLADAÇALIŞIR, YEŞİM HÜLYA UZ, MELİKE SAPMAZ METİN, GÜLNUR KIZILAY ÖZFİDAN

Kanser tedavisinde curcuminin yeri

Bitkisel ajanlar alternatif ve tamamlayıcı tıpta en çok kullanılan ürünlerdendir. Curcumin, Curcuma longa bitki-sinin yumrularından elde edilen sarı renkli bir pigmenttir. Curcuminin antikanser bir ajan olarak; deri, meme bez-leri, oral kavite, mide, özofagus, bağırsak, kolon, akciğer ve karaciğerde tümörogenezi baskıladığı bazı çalışma-larda gösterilmiştir. Ayrıca curcuminin radyoterapinin etkisini artırmak sureti ile tedaviden daha hızlı sonuç alınmasını sağladığı gösterilmiştir. Bu etkilerine ilaveten antioksidan özellik göstermesiyle de alkolün, ilaçların, radyasyonun, ağır metallerin normal dokular üzerinde oluşturduğu hasarları önleyici etkisini vurgulayan pek çok çalışma mevcuttur. Bu derlemede, curcuminin anti-kanser özellikleri ve radyoprotektif etkileri üzerinde durularak, yapılan çalışmalardan elde edilen sonuçlar özetlenmiştir.

The use of curcumin in cancer treatment

Herbal agents are the most widely used products in alternative and complementary medicine. Curcumin is a yellow pigment derived from the Curcuma longa tuber. As an anticancer agent, curcumin has been found in a number of studies to suppress tumorigenesis in cancers of the skin, breast glands, oral cavity, stomach, esophagus, bowel, colon, lung, and liver. Moreover, curcumin treatment also enhances the effectiveness of radiotherapy. In addition to its antitumor effects, curcumin also has effects on normal tissues. Many studies have demonstrated an effect of the antioxidant properties of curcumin on reducing damage induced by alcohol, drugs, radiation, heavy metals, etc. In this paper, the anticancer properties of curcumin, together with its radioprotective effects, are reviewed. The results obtained from a number of clinical studies using curcumin are also summarized.

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1. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003;3: 768-80.
2. Limtrakul P, Lipigorngoson S, Namwong O, Apisariyakul A, Dunn FW. Inhibitory effect of dietary curcuminon skin carcinogenesis in mice. Cancer Lett 1997;116: 197-203.
3. Priyadarsini KI. Free radical reactions of curcumin in membrane models. Free Radic Biol Med 1997;23: 838-43.
4. Piper JT, Singhal SS, Salameh MS, Torman RT, Awasthi YC, Awasthi S. Mechanisms of anticarcinogenic properties of curcumin: the effect of curcumin on glutathione linked detoxification enzymes in rat liver. Int J Biochem Cell Biol 1998;30: 445-56.
5. Huang MT, Smart RC, Wong CQ, Conney AH. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 1988;48: 5941-6.
6. Kuttan R, Bhanumathy P, Nirmala K, George MC. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett 1985;29: 197-202.
7. Kuttan R, Sudheeran PC, Joseph CD. Turmeric and curcumin as topical agents in cancer therapy. Tumori 1987;73: 29-31.
8. Rao TS, Basu N, Seth SD, Siddiqui HH. Some aspects of pharmacological profile of sodium curcuminate. Indian J Physiol Pharmacol 1984;28: 211-5.
9. Lee SL, Huang WJ, Lin WW, Lee SS, Chen CH. Preparation and anti-inflammatory activities of diarylheptanoid and diarylheptylamine analogs. Bioorg Med Chem 2005;13: 6175-81.
10. Chuang SE, Kuo ML, Hsu CH, Chen CR, Lin JK, Lai GM, et al. Curcumincontaining diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis 2000;21: 331-5.
11. Deshpande SS, Ingle AD, Maru GB. Chemopreventive efficacy of curcumin-free aqueous turmeric extract in 7,12-dimethylbenz[a] anthracene-induced rat mammary tumorigenesis. Cancer Lett 1998;123: 35-40.
12. Ushida J, Sugie S, Kawabata K, Pham QV, Tanaka T, Fujii K, et al. Chemopreventive effect of curcumin on N-nitrosomethylbenzylamine-147induced esophageal carcinogenesis in rats. Jpn J Cancer Res 2000;91: 893-8.
13. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 2008;65: 1631-52.
14. Akpolat M, Kanter M, Uzal MC. Protective effects of curcumin against gamma radiation-induced ileal mucosal damage. Arch Toxicol 2009;83: 609-17.
15. Anto RJ, Mukhopadhyay A, Denning K, Aggarwal BB. Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 2002;23: 143-50.
16. Mohandas KM, Desai DC. Epidemiology of digestive tract cancers in India. V. Large and small bowel. Indian J Gastroenterol 1999;18: 118-21.
17. Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 2001;7: 1894-1900.
18. Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res 2005;11:7490-8.
19. Thangapazham RL, Sharma A, Maheshwari RK. Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J 2006;8:443-9.
20. Garcea G, Berry DP, Jones DJ, Singh R, Dennison AR, Farmer PB, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev 2005;14: 120-5.
21. Kuo ML, Huang TS, Lin JK. Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim Biophys Acta 1996;1317: 95-100.
22. Ranjan D, Johnston TD, Reddy KS, Wu G, Bondada S, Chen C. Enhanced apoptosis mediates inhibition of EBV-transformed lymphoblastoid cell line proliferation by curcumin. J Surg Res 1999;87: 1-5.
23. Piwocka K, Zablocki K, Wieckowski MR, Skierski J, Feiga I, Szopa J, et al. A novel apoptosis-like pathway, independent of mitochondria and caspases, induced by curcumin in human lymphoblastoid T (Jurkat) cells. Exp Cell Res 1999;249: 299-307.
24. Han SS, Chung ST, Robertson DA, Ranjan D, Bondada S. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin Immunol 1999;93: 152-61.
25. Chen H, Zhang ZS, Zhang YL, Zhou DY. Curcumin inhibits cell proliferation by interfering with the cell cycle and inducing apoptosis in colon carcinoma cells. Anticancer Res 1999;19: 3675-80.
26. Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999;59: 597-601.
27. Korutla L, Kumar R. Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells. Biochim Biophys Acta 1994;1224: 597-600.
28. Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factorkappaB signaling. Int J Cancer 2004;111: 679-92.
29. Shishodia S, Amin HM, Lai R, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol 2005;70: 700-13.
30. Sen S, Sharma H, Singh N. Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. Biochem Biophys Res Commun 2005;331: 1245-52.
31. Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. Multiple biological activities of curcumin: a short review. Life Sci 2006;78: 2081-7.
32. Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R. Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Lett 1995;94: 79-83.
33. Singh SV, Hu X, Srivastava SK, Singh M, Xia H, Orchard JL, et al. Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin. Carcinogenesis 1998;19: 1357-60.
34. Deshpande SS, Ingle AD, Maru GB. Inhibitory effects of curcumin-free aqueous turmeric extract on benzo[a]pyrene-induced forestomach papillomas in mice. Cancer Lett 1997;118: 79-85.
35. Azuine MA, Bhide SV. Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice. Nutr Cancer 1992;17: 77-83.
36. Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res 1994;54: 5841-7.
37. Ikezaki S, Nishikawa A, Furukawa F, Kudo K, Nakamura H, Tamura K, et al. Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride in rats. Anticancer Res 2001;21: 3407-11.
38. Busquets S, Carbo N, Almendro V, Quiles MT, Lopez-Soriano FJ, Argiles JM. Curcumin, a natural product present in turmeric, decreases tumor growth but does not behave as an anticachectic compound in a rat model. Cancer Lett 2001;167: 33-8.
39. Menon LG, Kuttan R, Kuttan G. Inhibition of lung metastasis in mice induced by B16F10 melanoma cells by polyphenolic compounds. Cancer Lett 1995;95: 221–5.
40. Dorai T, Cao YC, Dorai B, Buttyan R, Katz AE. Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo. Prostate 2001;47: 293-303.
41. Toda S, Miyase T, Arichi H, Tanizawa H, Takino Y. Natural antioxidants. III. Antioxidative components isolated from rhizome of Curcuma longa L. Chemical and Pharmaceutical Bulletin 1985;33: 1725-8.
42. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine 1995;1: 27-31.
43. Thaloor D, Miller KJ, Gephart J, Mitchell PO, Pavlath GK. Systemic administration of the NF-κB inhibitor curcumin stimulates muscle regeneration after traumatic injury. American Journal of Physiology Cell Physiology 1999;277: 320-9.
44. Hahm ER, Gho YS, Park S, Park C, Kim KW, Yang CH. Synthetic curcumin analogs inhibit activator protein-1 transcription and tumor-induced angiogenesis. Biochemical Biophysical Research Communication 2004;321: 337–44.
45. Arbiser JL, Klauber N, Rohan R, van Leeuwen R, Huang MT, Fisher C, et al. Curcumin is an in vivo inhibitor of angiogenesis. Molecular Medicine 1998;4: 376-83.
46. Mohan R, Sivak J, Ashton P, Russo LA, Pham BQ, Kasahara N, et al. Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. Journal of Biological Chemistry 2000;275: 10405-12.
47. Shim JS, Kim JH, Cho HY, Yum YN, Kim SH, Park HJ, et al. Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin. Chem Biol 2003;10: 695-704.
48. Dorai T, Gehani N, Katz A. Therapeutic potential of curcumin in human prostate cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein. Mol Urol 2000;4: 1-6.
49. Varadkar P, Dubey P, Krishna M, Verma N. Modulation of radiation-induced protein kinase C activity by phenolics. J Radiol Prot 2001;21: 361-70.
50. Khopde SM, Priyadarsini KI, Guha SN, Satav JG, Venkatesan P, Rao MN. Inhibition of radiation-induced lipid peroxidation by tetrahydrocurcumin: possible mechanisms by pulse radiolysis. Biosci Biotechnol Biochem 2000;64: 503-9.
51. Subramanian M, Sreejayan, Rao MN, Devasagayam TP, Singh BB. Diminution of singlet oxygen-induced DNA damage by curcumin and related antioxidants. Mutat Res 1994;311: 249-55.
52. Biswas SK, McClure D, Jimenez LA, Megson IL, Rahman I. Curcumin induces glutathione biosynthesis and inhibits NF-kappaB activation and interleukin-8 release in alveolar epithelial cells: mechanism of free radical scavenging activity. Antioxid Redox Signal 2005;7: 32-41.
53. Thresiamma KC, George J, Kuttan R. Protective effect of curcumin, ellagic acid and bixin on radiation induced toxicity. Indian J Exp Biol 1996;34: 845-7.
54. Thresiamma KC, George J, Kuttan R. Protective effect of curcumin, ellagic acid and bixin on radiation induced genotoxicity. J Exp Clin Cancer Res 1998;17: 431-4.
55. Jagetia GC, Venkatesh P, Baliga MS. Fruit extract of Aegle marmelos protects mice against radiation-induced lethality. Integr Cancer Ther 2004;3: 323-32.
56. Inano H, Onoda M. Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2’-deoxyguanosine, tumorigenesis, but not mortality, induced by gamma-ray irradiation. Int J Radiat Oncol Biol Phys 2002;53: 735-43.
57. Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, et al. Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol Biol Phys 2006;65: 890-8.
58. Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene 2004;23: 1599-607.
59. Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001;21: 2895–900.
60. Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2006;4: 1035-8.
61. Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin.Cancer Res 2004;10: 6847-54.
62. Gafner S, Lee SK, Cuendet M, Barthelemy S, Vergnes L, Labidalle S, et al. Biologic evaluation of curcumin and structural derivatives in cancer chemoprevention model systems. Phytochemistry 2004;65: 2849-59.