A Review on Therapeutic Potentials of Crocetin-A Carotenoid Derived from Saffron
Abstract
Natural dyes recognized as carotenoids have found application in health care system due to their wide biological activities, high safety margins and lower cost. Crocetin, a carotenoid constituent of saffron has shown wide range of pharmacological applications due to its significant antioxidant properties. It is used as antifungal, antimicrobial and antiallergic agent. Crocetin has shown significant potential as an anti- tumor agent in animal models and cell culture systems.
Current review has shown crocetin’s multispectrum pharmacological benefits for the treatment of various chronic diseases such as cancer, diabetes, parkinson’s and alzheimer’s disease. This review focus on various studies done on crocetin explaining its broa d spectrum pharmacological activities. In addition, this review will also focus on the pharmacokinetic studies of crocetin on human and animals. Crocetin is a highly potent molecule because of its strong antioxidant properties. In the near future, increasing its bioavailability using novel drug delivery methods having minimum side effects will get this promising natural molecule to the forefront of therapy for the treatment of various chronic human diseases like cancer, diabetes, parkinson’s and alzheimer’s disease.
Keywords:
Carotenoid, Antioxidant, Anticancer, Anti-alzheimer, Antidiabetic, Crocetin
References
1. Abdullaev FI, Espinosa-Aguirre JJ. Biomedical properties of saffron and its potential use of cancer therapy and chemopreventive trials. Cancer Detect. Prev. 2004;28:426–432.
2. Abdullaev FI, Frenkel GD. Effect of saffron on cell colony formation and cellular nucleic acid and protein synthesis. Biofactors. 1992;3:201–204.
3. Abdullaev FI. Inhibitory effect of crocetin on intracellular nucleic acid and protein synthesis in malignant cells.Toxicol. Lett. 1994;70:243–251.
4. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol. 2006;71:1397–1421.
5. Ahmad AS, Ansari MA, Ahmad M, Saleem S, Yousuf S, Hoda MN, Islam F. Neuroprotection by crocetin in a hemi-parkinsonian rat model. PharmacolBiochemBehav. 2005;81:805–813.
6. Akhondzadeh S, Sabet MS, Harirchian M, Togha M, Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi M, Alimardani R, Jamshidi A. Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16‐week, randomized and placebo‐controlled trial. J Clin Pharm Therapeut. 2010a; 35:581–588.
7. Aung HH, Wang CZ, Ni M, Fishbein A, Mehendale SR, Xie JT, Shoyama CY, Yuan CS. CrocinfromCrocussativus possesses significant anti-proliferation effects on human colorectal cancer cells. Exp. Oncol.2007;29:175–180.
8. Bathaie S, Hoshyar R, Miri H, Sadeghizadeh M. Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer, June 2013, 397-403.
9. Bhargavak V, Medicinal uses and pharmacological properties of crocus sativuslinn(saffron), April 2011; 98-101
10. Bhat JV, Broker R. Riboflavine and thiamine contents of saffron Crocus Sativus. Nature. 1953;172:544–545.
11. Cao W, Cui J, Li S, Zhang D, Guo Y, Li Q, Luan Y, Liu X.Crocetin restores diabetic endothelial progenitor cell disfunction by enhancing NO bioavailability via regulation of P13K/AKT-eNOS and ROS pathways, May 2017; 213-220.
12. Chang W-C, Lin Y-L, Lee M-J, Shiow S-J, Wang C-J. Inhibitory effect of crocetin on benzo(a)pyrenegenotoxicity and neoplastic transformation in C3H10T1/2 cells. Anticancer Res. 1996;16:3603–3608.
13. Chryssanthi DG, Lamari FN, Iatrou G, Pylara A, Karamanos NK, Cordopatis P. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer Res. 2007;27:357–362.
14. Dhar A, Mehta S, Dhar G, Dhar K, Banerjee S, Van Veldhuizen P, Campbell DR, Banerjee SK. Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mice model. Mol. Cancer Ther.2009;8:315–323.
15. Emidio G, Rossi G, Bonomo I, Alonso G, Sferra R, Vetuschi A, Artini P, Provenzani A, Falone S, Carta G, Alessandro A, Amicarelli F, Tatone C. The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers, November 2017;397-405.
16. Elgazar A, Rezq A, andBukhari HM. Anti-Hyperglycemic Effect of Saffron Extract in Alloxan-Induced Diabetic Rats, European Journal of Biological Sciences 5 (1): 14-22, 2013.
17. Escribano J, Alonso GL, Coca-Prados M, Fernandez JA. Crocin, safranal and picrocrocin from saffron (Crocus sativus L) inhibit the growth of human cancer cells in vitro. Cancer Lett. 1996;100:23–30.
18. Farkhondeh T andSamarghandian S. The effect of saffron (Crocus sativus L.) and its ingredients on the management of diabetes mellitus and dislipidemia, Vol. 8(20), pp. 541-549, 29 May, 2014.
19. Fernandez J, Anticancer properties of saffron, Crocus sativus Linn. 2006, Pages 313-330.
20. Gainer JL, Wallis DA, Jones JR. The effect of skin papilloma and rous sarcoma. Oncology. 1976;33:222–224.
21. Gutheil W, Reed G, Ray A, Dhar A.Crocetin: an agent derived from saffron for prevention and therapy for cancer, 2015, 173-179.
22. Hosseini A, Razavi BM, Hosseinzadeh H. Pharmacokinetic Properties of Saffron and its Active Components, Eur J Drug MetabPharmacokinet 43(4), 383-390, 2017.
23. Kanakis CD, Tarantilis PA, Tajmir-Riahi HA, Polissiou MG. Interaction of tRNA with safranal, crocetin and dimethylcrocetin. J. Biomol. Struct. Dynam. 2007;24:537–545.
24. Khazdair M, Boskabady M, Hosseini M, Rezaee R, Tsatsakis A. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review, 2015 Sep-Oct; 5(5): 376–391.
25. Kim-Jun H. Inhibitory effects of alpha and beta carotene on croton oil-induced or enzymatic lipid peroxidation and hydrogen peroxide production in mouse epidermis. Int. J. Biochem. 1993;25:911–915.
26. Kunnumakkara AB, Anand P, Harikumar KB, Aggarwal BB. In: DNA damage and cancer prevention by polyphenols: Chemoprevention of cancer and DNA damage by dietary factors. Knasmüller S, Demarini DM, Johnson I, Gerhauser C, editors. Wiley-VCH; Weinheim: 2009. pp. 455–482.
27. Lautenschläger M, Hüwel S, Lechtenberg M, Hensel A, Hans-Joachi G.In vitro absorption studies of saffron ingredients (tr-Crocin-1, tr-Crocetin) in the Caco-2 and blood-brain barrier model, 2013;230-239.
28. Magesh V, Singh JP, Selvendiran K, Ekambaram B, Sakthisekaran D. Antitumor activity of crocetin in accordance to tumor incidence, antioxidant status, drug metabolizing enzymes and histopathological studies. Mol. Cell. Biochem. 2006;287:127–135.
29. Magesh V, Durgabhavani K, Senthilnathan P, Rajendran P, Sakthisekaran D. In vivo protective effect of crocetin on benzo(a)pyrene induced lung cancer in swiss albino mice. Phytother. Res. 2009;23:533–539.
30. Morjani H, Tarantilis P, Polissiou M, Manfeit M. Growth inhibition and induction of inhibition of erythroid differentiation activity by crocin, dimethyl-crocetine and β-carotene on K562 cells. Anticancer Res.1990;10:1398–1406.
31. Mousavi SH, Tavakkol-Afshari J, Brook A, Jafari-Anarkooli I. Role of capases and Bax protein in saffron-induced apoptosis in MCF-7 cells. Food Chem. Toxicol. 2009;47:1909–1913.
32. Nair SC, Kurumboor SK, Hasegawa JH. Saffron chemoprevention in biology and medicine: a review. Cancer Biother. 1995;10:257–264.
33. Nair SC, Pannikar B, Panikkar KR. Antitumor activity of saffron (Crocus sativus) Cancer Lett.1991;57:109–114.
34. Nassiri-Asl M., Hosseinzadeh H., Neuropharmacology Effects of Saffron (Crocus sativus) and Its Active Constituents, Chapter 3; 215-221.
35. Purushothuman S, Nandasena C, Peoples CL, El Massri N, Johnstone DM, Mitrofanis J, Stone J. Saffron pre-treatment offers neuroprotection to Nigral and retinal dopaminergic cells of MPTP-Treated mice. J Parkinsons Dis., 321-334
36. Rahaiee S, Moini S, Hashemi M, Shojaosadati S. Evaluation of antioxidant activities of bioactive compounds and various extracts obtained from saffron (Crocus sativus L.): a review,2015 Apr; 52(4): 1881–1888.
37. Robinson J.Crocetin sources, health benefits and uses, Naturalpedia, Tuesday, October 24, 2017; 256-278.
38. Tarantilis PA, Morjani H, Pollissiou M, Manfeit M. Inhibition of growth and induction of differentiation of promyelocyticleukemia (HL-60) by caratenoids from Crocus sativus L. Anticancer Res. 1994;14:1913–1918.
39. Tavakkol-Afshari J, Brook A, Mousavi SH. Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Food Chem. Toxicol. 2008;46:3443–3447.
40. Tribuzi R, Crispoltoni L, Chiurchiu V, Casella A, Montecchiani C, Pino A, Maccarrone M, Palmerini C, Caltagirone C, Kawarai T, Orlacchio A, Orlacchio A. Trans-crocetin improves amyloid-β degradation in monocytes from Alzheimer’s disease patients, Nov 2016; 234-247.
41. Tseng TH, Chu CY, Huang JM, Shiow SJ, Wang CJ. Crocetin protects against oxidative damage in rat primary hepatocytes. Cancer Lett. 1995;97:61–67.
42. Shen XC, Qian ZY, Effects of crocetin on antioxidant enzymatic activities in cardiac hypertrophy induced by norepinephrine in rats,2006 Apr; 61(4):348-352.
43. Unnikrishnan MC, Kuttan R. Tumor reducing and anticarcinogenic activity of selected spices. Cancer Lett.1990;51:85–89.
44. Wang CJ, Shiah HS, Lin JK. Modulatory effect of crocetin on aflatoxin B1 cytotoxicity and DNA adduct formation in C3H10T1/2 fibroblast cell. Cancer Lett. 1991;56:1–10.
45. Wang CJ, Shiow SJ, Lin JK. Effects of crocetin on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. Carcinogenesis. 1991;12:459–462.
46. Wang CJ, Hsu JD, Lin JK. Suppression of aflatoxin B1-induced lesions by crocetin (a natural carotenoid)Carcinogenesis. 1991;12:1807–1810.
47. Yoshino F, Yoshida A, Umigai N, Kubo K, Lee M.Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain, 2011, 182-187.
48. Zhou C, Bai W, Chen Q, Xu Z, Zhu X, Wen A, Yang X. Protective effect of crocetin against burn-induced intestinal injury, June 2015, 99-107.
2. Abdullaev FI, Frenkel GD. Effect of saffron on cell colony formation and cellular nucleic acid and protein synthesis. Biofactors. 1992;3:201–204.
3. Abdullaev FI. Inhibitory effect of crocetin on intracellular nucleic acid and protein synthesis in malignant cells.Toxicol. Lett. 1994;70:243–251.
4. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol. 2006;71:1397–1421.
5. Ahmad AS, Ansari MA, Ahmad M, Saleem S, Yousuf S, Hoda MN, Islam F. Neuroprotection by crocetin in a hemi-parkinsonian rat model. PharmacolBiochemBehav. 2005;81:805–813.
6. Akhondzadeh S, Sabet MS, Harirchian M, Togha M, Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi M, Alimardani R, Jamshidi A. Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16‐week, randomized and placebo‐controlled trial. J Clin Pharm Therapeut. 2010a; 35:581–588.
7. Aung HH, Wang CZ, Ni M, Fishbein A, Mehendale SR, Xie JT, Shoyama CY, Yuan CS. CrocinfromCrocussativus possesses significant anti-proliferation effects on human colorectal cancer cells. Exp. Oncol.2007;29:175–180.
8. Bathaie S, Hoshyar R, Miri H, Sadeghizadeh M. Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer, June 2013, 397-403.
9. Bhargavak V, Medicinal uses and pharmacological properties of crocus sativuslinn(saffron), April 2011; 98-101
10. Bhat JV, Broker R. Riboflavine and thiamine contents of saffron Crocus Sativus. Nature. 1953;172:544–545.
11. Cao W, Cui J, Li S, Zhang D, Guo Y, Li Q, Luan Y, Liu X.Crocetin restores diabetic endothelial progenitor cell disfunction by enhancing NO bioavailability via regulation of P13K/AKT-eNOS and ROS pathways, May 2017; 213-220.
12. Chang W-C, Lin Y-L, Lee M-J, Shiow S-J, Wang C-J. Inhibitory effect of crocetin on benzo(a)pyrenegenotoxicity and neoplastic transformation in C3H10T1/2 cells. Anticancer Res. 1996;16:3603–3608.
13. Chryssanthi DG, Lamari FN, Iatrou G, Pylara A, Karamanos NK, Cordopatis P. Inhibition of breast cancer cell proliferation by style constituents of different Crocus species. Anticancer Res. 2007;27:357–362.
14. Dhar A, Mehta S, Dhar G, Dhar K, Banerjee S, Van Veldhuizen P, Campbell DR, Banerjee SK. Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mice model. Mol. Cancer Ther.2009;8:315–323.
15. Emidio G, Rossi G, Bonomo I, Alonso G, Sferra R, Vetuschi A, Artini P, Provenzani A, Falone S, Carta G, Alessandro A, Amicarelli F, Tatone C. The Natural Carotenoid Crocetin and the Synthetic Tellurium Compound AS101 Protect the Ovary against Cyclophosphamide by Modulating SIRT1 and Mitochondrial Markers, November 2017;397-405.
16. Elgazar A, Rezq A, andBukhari HM. Anti-Hyperglycemic Effect of Saffron Extract in Alloxan-Induced Diabetic Rats, European Journal of Biological Sciences 5 (1): 14-22, 2013.
17. Escribano J, Alonso GL, Coca-Prados M, Fernandez JA. Crocin, safranal and picrocrocin from saffron (Crocus sativus L) inhibit the growth of human cancer cells in vitro. Cancer Lett. 1996;100:23–30.
18. Farkhondeh T andSamarghandian S. The effect of saffron (Crocus sativus L.) and its ingredients on the management of diabetes mellitus and dislipidemia, Vol. 8(20), pp. 541-549, 29 May, 2014.
19. Fernandez J, Anticancer properties of saffron, Crocus sativus Linn. 2006, Pages 313-330.
20. Gainer JL, Wallis DA, Jones JR. The effect of skin papilloma and rous sarcoma. Oncology. 1976;33:222–224.
21. Gutheil W, Reed G, Ray A, Dhar A.Crocetin: an agent derived from saffron for prevention and therapy for cancer, 2015, 173-179.
22. Hosseini A, Razavi BM, Hosseinzadeh H. Pharmacokinetic Properties of Saffron and its Active Components, Eur J Drug MetabPharmacokinet 43(4), 383-390, 2017.
23. Kanakis CD, Tarantilis PA, Tajmir-Riahi HA, Polissiou MG. Interaction of tRNA with safranal, crocetin and dimethylcrocetin. J. Biomol. Struct. Dynam. 2007;24:537–545.
24. Khazdair M, Boskabady M, Hosseini M, Rezaee R, Tsatsakis A. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review, 2015 Sep-Oct; 5(5): 376–391.
25. Kim-Jun H. Inhibitory effects of alpha and beta carotene on croton oil-induced or enzymatic lipid peroxidation and hydrogen peroxide production in mouse epidermis. Int. J. Biochem. 1993;25:911–915.
26. Kunnumakkara AB, Anand P, Harikumar KB, Aggarwal BB. In: DNA damage and cancer prevention by polyphenols: Chemoprevention of cancer and DNA damage by dietary factors. Knasmüller S, Demarini DM, Johnson I, Gerhauser C, editors. Wiley-VCH; Weinheim: 2009. pp. 455–482.
27. Lautenschläger M, Hüwel S, Lechtenberg M, Hensel A, Hans-Joachi G.In vitro absorption studies of saffron ingredients (tr-Crocin-1, tr-Crocetin) in the Caco-2 and blood-brain barrier model, 2013;230-239.
28. Magesh V, Singh JP, Selvendiran K, Ekambaram B, Sakthisekaran D. Antitumor activity of crocetin in accordance to tumor incidence, antioxidant status, drug metabolizing enzymes and histopathological studies. Mol. Cell. Biochem. 2006;287:127–135.
29. Magesh V, Durgabhavani K, Senthilnathan P, Rajendran P, Sakthisekaran D. In vivo protective effect of crocetin on benzo(a)pyrene induced lung cancer in swiss albino mice. Phytother. Res. 2009;23:533–539.
30. Morjani H, Tarantilis P, Polissiou M, Manfeit M. Growth inhibition and induction of inhibition of erythroid differentiation activity by crocin, dimethyl-crocetine and β-carotene on K562 cells. Anticancer Res.1990;10:1398–1406.
31. Mousavi SH, Tavakkol-Afshari J, Brook A, Jafari-Anarkooli I. Role of capases and Bax protein in saffron-induced apoptosis in MCF-7 cells. Food Chem. Toxicol. 2009;47:1909–1913.
32. Nair SC, Kurumboor SK, Hasegawa JH. Saffron chemoprevention in biology and medicine: a review. Cancer Biother. 1995;10:257–264.
33. Nair SC, Pannikar B, Panikkar KR. Antitumor activity of saffron (Crocus sativus) Cancer Lett.1991;57:109–114.
34. Nassiri-Asl M., Hosseinzadeh H., Neuropharmacology Effects of Saffron (Crocus sativus) and Its Active Constituents, Chapter 3; 215-221.
35. Purushothuman S, Nandasena C, Peoples CL, El Massri N, Johnstone DM, Mitrofanis J, Stone J. Saffron pre-treatment offers neuroprotection to Nigral and retinal dopaminergic cells of MPTP-Treated mice. J Parkinsons Dis., 321-334
36. Rahaiee S, Moini S, Hashemi M, Shojaosadati S. Evaluation of antioxidant activities of bioactive compounds and various extracts obtained from saffron (Crocus sativus L.): a review,2015 Apr; 52(4): 1881–1888.
37. Robinson J.Crocetin sources, health benefits and uses, Naturalpedia, Tuesday, October 24, 2017; 256-278.
38. Tarantilis PA, Morjani H, Pollissiou M, Manfeit M. Inhibition of growth and induction of differentiation of promyelocyticleukemia (HL-60) by caratenoids from Crocus sativus L. Anticancer Res. 1994;14:1913–1918.
39. Tavakkol-Afshari J, Brook A, Mousavi SH. Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Food Chem. Toxicol. 2008;46:3443–3447.
40. Tribuzi R, Crispoltoni L, Chiurchiu V, Casella A, Montecchiani C, Pino A, Maccarrone M, Palmerini C, Caltagirone C, Kawarai T, Orlacchio A, Orlacchio A. Trans-crocetin improves amyloid-β degradation in monocytes from Alzheimer’s disease patients, Nov 2016; 234-247.
41. Tseng TH, Chu CY, Huang JM, Shiow SJ, Wang CJ. Crocetin protects against oxidative damage in rat primary hepatocytes. Cancer Lett. 1995;97:61–67.
42. Shen XC, Qian ZY, Effects of crocetin on antioxidant enzymatic activities in cardiac hypertrophy induced by norepinephrine in rats,2006 Apr; 61(4):348-352.
43. Unnikrishnan MC, Kuttan R. Tumor reducing and anticarcinogenic activity of selected spices. Cancer Lett.1990;51:85–89.
44. Wang CJ, Shiah HS, Lin JK. Modulatory effect of crocetin on aflatoxin B1 cytotoxicity and DNA adduct formation in C3H10T1/2 fibroblast cell. Cancer Lett. 1991;56:1–10.
45. Wang CJ, Shiow SJ, Lin JK. Effects of crocetin on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. Carcinogenesis. 1991;12:459–462.
46. Wang CJ, Hsu JD, Lin JK. Suppression of aflatoxin B1-induced lesions by crocetin (a natural carotenoid)Carcinogenesis. 1991;12:1807–1810.
47. Yoshino F, Yoshida A, Umigai N, Kubo K, Lee M.Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain, 2011, 182-187.
48. Zhou C, Bai W, Chen Q, Xu Z, Zhu X, Wen A, Yang X. Protective effect of crocetin against burn-induced intestinal injury, June 2015, 99-107.
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How to Cite
Priya, Shobhit kumar, and S K Gupta. “A Review on Therapeutic Potentials of Crocetin-A Carotenoid Derived from Saffron”. Current Research in Pharmaceutical Sciences, Vol. 9, no. 4, Jan. 2020, pp. 54-62, doi:10.24092/CRPS.2019.090401.
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Review Articles
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