Crocetin regulates cell cycle progression in N-nitroso-N-methylurea(NMU)-induced breast cancer in rat: cyclin D1 suppression, p21Cip1 and p53 induction
Crocetin regulates cell cycle markers in rats breast cancer
,
Abstract
Objective: Crocetin, a saffron-derived carotenoid, inhibited tumor growth in some cancer types. However, its mechanism of action still needs to be clearly understood. Here, the Crocetin effect on the expression of some cell cycle regulators was investigated.
Methods: The N-nitroso-N-methylurea (NMU)-induced rat mammary carcinomas were induced in a group of 35-day-old female Wistar Albino rats. Then, the expression of several cell cycle regulators was studied using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. After the tumor appearance, these rats were treated with Crocetin through weekly, intraperitoneal injections of 100 mg/kg body weight for four weeks. A control group has received the vehicle only. In the end, rats were sacrificed, and tumors were divided into two parts. A part was for pathologic investigation, and a part was retained at -70 °C to determine desired parameters.
Results: Before Crocetin treatment, the tumor volumes were 13.27 ± 3.77 and 9.44 ± 4.39 cm3, which was changed to 23.66 ± 8.82 and 4.71 ± 2.44 cm3 at the end of the experiment in the untreated and treated groups, respectively. The results showed that Crocetin markedly decreased the increased expression of cyclin D1 due to NMU administration. However, it further increased the expression of p53 and p21Cip1, with no significant effect on p27Kip1 expression. We previously showed Crocin-induced cell cycle arrest through a p53-dependent mechanism.
Conclusions. Crocetin induced the cell cycle arrest in NMU-induced breast cancer in rats through a p53-independent mechanism. It is the second mechanism additional to apoptosis induction in cancer cells.
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3. Sun, Y., H.J. Xu, Y.X. Zhao, L.Z. Wang, L.R. Sun, Z. Wang, et al., Crocin Exhibits Antitumor Effects on Human Leukemia HL-60 Cells In Vitro and In Vivo. Evid Based Complement Alternat Med, 2013. 2013: p. 690164.
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7. He, K., P. Si, H. Wang, U. Tahir, K. Chen, J. Xiao, et al., Crocetin induces apoptosis of BGC-823 human gastric cancer cells. Mol Med Rep, 2014. 9(2): p. 521-6.
8. Taheri, F., S.Z. Bathaie, M. Ashrafi, and E. Ghasemi, Assessment of Crocin Toxicity on the Rat Liver. mdrsjrns, 2014. 17(3): p. 67-79.
9. Mousavi, B., S.Z. Bathaie, F. Fadai, Z. Ashtari, N. Ali Beigi, S. Farhang, et al., Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed, 2015. 5(5): p. 413-9.
10. Sanjari-Pour, M., N. Faridi, P. Wang, and S.Z. Bathaie, Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy. Phytother Res, 2023.
11. Sajjadi, M. and Z. Bathaie, Comparative Study on The Preventive Effect of Saffron Carotenoids, Crocin and Crocetin, in NMU-Induced Breast Cancer in Rats. Cell J, 2017. 19(1): p. 94-101.
12. Ashrafi, M., S.Z. Bathaie, M. Taghikhani, and A.A. Moosavi-Movahedi, The effect of carotenoids obtained from saffron on histone H1 structure and H1-DNA interaction. Int J Biol Macromol, 2005. 36(4): p. 246-52.
13. Chitsazan, A., S.Z. Bathaie, M.A. Mohagheghi, and S. Banasadegh. Rat mammary tumor induced by NMU and the effect of natural carotenoids. in XXX1st Symposium on hormones and regulation: cancer cell signalling. 2006. Hostellerie du Mont Sainte Odile, Ottrott, France.
14. Shibamoto, Y. and S. Takano, Non-Surgical Definitive Treatment for Operable Breast Cancer: Current Status and Future Prospects. Cancers (Basel), 2023. 15(6).
15. Riis, M., Modern surgical treatment of breast cancer. Ann Med Surg (Lond), 2020. 56: p. 95-107.
16. Mazurakova, A., L. Koklesova, M. Samec, E. Kudela, K. Kajo, V. Skuciova, et al., Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care. Epma j, 2022. 13(2): p. 315-334.
17. Younas, M., C. Hano, N. Giglioli-Guivarc'h, and B.H. Abbasi, Mechanistic evaluation of phytochemicals in breast cancer remedy: current understanding and future perspectives. RSC Advances, 2018. 8(52): p. 29714-29744.
18. Bathaie, S.Z., N. Faridi, A. Nasimian, H. Heidarzadeh, and F. Tamanoi, How Phytochemicals Prevent Chemical Carcinogens and/or Suppress Tumor Growth? Enzymes, 2015. 37: p. 1-42.
19. Bolhassani, A., A. Khavari, and S.Z. Bathaie, Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochim Biophys Acta, 2014. 1845(1): p. 20-30.
20. Bathaie, S.Z. and S.Z. Mousavi, New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nutr, 2010. 50(8): p. 761-86.
21. Mousavi, S.H., J. Tavakkol-Afshari, A. Brook, and I. Jafari-Anarkooli, Role of caspases and Bax protein in saffron-induced apoptosis in MCF-7 cells. Food Chem Toxicol, 2009. 47(8): p. 1909-13.
22. D'Alessandro, A.M., A. Mancini, A.R. Lizzi, A. De Simone, C.E. Marroccella, G.L. Gravina, et al., Crocus sativus stigma extract and its major constituent crocin possess significant antiproliferative properties against human prostate cancer. Nutr Cancer, 2013. 65(6): p. 930-42.
23. Bathaie, S.Z., R. Hoshyar, H. Miri, and M. Sadeghizadeh, Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer. Biochem Cell Biol, 2013. 91(6): p. 397-403.
24. Dhar, A., S. Mehta, G. Dhar, K. Dhar, S. Banerjee, P. Van Veldhuizen, et al., Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. Mol Cancer Ther, 2009. 8(2): p. 315-23.
25. Magesh, V., J.P. Singh, K. Selvendiran, G. Ekambaram, and D. Sakthisekaran, Antitumour activity of crocetin in accordance to tumor incidence, antioxidant status, drug metabolizing enzymes and histopathological studies. Mol Cell Biochem, 2006. 287(1-2): p. 127-35.
26. Montalto, F.I. and F. De Amicis, Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma. Cells, 2020. 9(12).
27. Barnes, D.M. and C.E. Gillett, Cyclin D1 in breast cancer. Breast Cancer Res Treat, 1998. 52(1-3): p. 1-15.
28. Rani, R., V.K. Kansal, D. Kaushal, and S. De, Dietary intervention of cow ghee and soybean oil on expression of cell cycle and apoptosis related genes in normal and carcinogen treated rat mammary gland. Mol Biol Rep, 2011. 38(5): p. 3299-307.
29. Liu, Q., W.T. Loo, S.C. Sze, and Y. Tong, Curcumin inhibits cell proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine, 2009. 16(10): p. 916-22.
30. Jang, T.J., J.H. Park, M.Y. Cho, and J.R. Kim, Chemically induced rat mammary tumor treated with tamoxifen showed decreased expression of cyclin D1, cyclin E, and p21(Cip1). Cancer Lett, 2001. 170(2): p. 109-16.
31. Zhao, P., C.L. Luo, X.H. Wu, H.B. Hu, C.F. Lv, and H.Y. Ji, [Proliferation apoptotic influence of crocin on human bladder cancer T24 cell line]. Zhongguo Zhong Yao Za Zhi, 2008. 33(15): p. 1869-73.
32. Moon, K.Y., N-nitroso-N-methylurea and N-nitroso-N-ethylurea induce upregulation of cellular NF-kappa B activity through protein kinase C-dependent pathway in human malignant keratinocytes. Arch Pharm Res, 2010. 33(1): p. 133-9.
33. Hinz, M., D. Krappmann, A. Eichten, A. Heder, C. Scheidereit, and M. Strauss, NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol, 1999. 19(4): p. 2690-8.
34. Yang, R., L. Yang, X. Shen, W. Cheng, B. Zhao, K.H. Ali, et al., Suppression of NF-kappaB pathway by crocetin contributes to attenuation of lipopolysaccharide-induced acute lung injury in mice. Eur J Pharmacol, 2012. 674(2-3): p. 391-6.
35. Oren, M. and V. Rotter, Introduction: p53--the first twenty years. Cell Mol Life Sci, 1999. 55(1): p. 9-11.
36. Marei, H.E., A. Althani, N. Afifi, A. Hasan, T. Caceci, G. Pozzoli, et al., p53 signaling in cancer progression and therapy. Cancer Cell International, 2021. 21(1): p. 703.
37. Dotto, G.P., p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta, 2000. 1471(1): p. M43-56.
38. Jang, T.J., M.S. Kang, H. Kim, D.H. Kim, J.I. Lee, and J.R. Kim, Increased expression of cyclin D1, cyclin E and p21(Cip1) associated with decreased expression of p27(Kip1) in chemically induced rat mammary carcinogenesis. Jpn J Cancer Res, 2000. 91(12): p. 1222-32.
39. Ashrafi, M., S.Z. Bathaie, and S. Abroun, High Expression of Cyclin D1 and p21 in N-Nitroso-N-Methylurea-Induced Breast Cancer in Wistar Albino Female Rats. Cell J, 2012. 14(3): p. 193-202.
40. Crist, K.A., R.D. Fuller, B. Chaudhuri, P. Chaudhuri, and M. You, Brief communication, P53 accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors. Toxicol Pathol, 1996. 24(3): p. 370-5.
41. Jassim, M.M.A., K.H. Rasool, and M.M. Mahmood, p53, p21, and cyclin d1 protein expression patterns in patients with breast cancer. Vet World, 2021. 14(10): p. 2833-2838.
42. Zohny, S.F., A.L. Al-Malki, M.A. Zamzami, and H. Choudhry, p21(Waf1/Cip1): its paradoxical effect in the regulation of breast cancer. Breast Cancer, 2019. 26(2): p. 131-137.
43. Thor, A.D., S. Liu, D.H. Moore, 2nd, Q. Shi, and S.M. Edgerton, p(21WAF1/CIP1) expression in breast cancers: associations with p53 and outcome. Breast Cancer Res Treat, 2000. 61(1): p. 33-43.
44. Zhong, Y.J., F. Shi, X.L. Zheng, Q. Wang, L. Yang, H. Sun, et al., Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms. Acta Pharmacol Sin, 2011. 32(12): p. 1529-36.
45. Vlach, J., S. Hennecke, and B. Amati, Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J, 1997. 16(17): p. 5334-44.
46. Slingerland, J. and M. Pagano, Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol, 2000. 183(1): p. 10-7.
2. Ashrafi, M., S.Z. Bathaie, S. Abroun, and M. Azizian, Effect of Crocin on Cell Cycle Regulators in N-Nitroso-N-Methylurea-Induced Breast Cancer in Rats. DNA Cell Biol, 2015.
3. Sun, Y., H.J. Xu, Y.X. Zhao, L.Z. Wang, L.R. Sun, Z. Wang, et al., Crocin Exhibits Antitumor Effects on Human Leukemia HL-60 Cells In Vitro and In Vivo. Evid Based Complement Alternat Med, 2013. 2013: p. 690164.
4. Xi, L., Z. Qian, P. Du, and J. Fu, Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats. Phytomedicine, 2007. 14(9): p. 633-6.
5. Hoshyar, R., S.Z. Bathaie, and M. Sadeghizadeh, Crocin triggers the apoptosis through increasing the Bax/Bcl-2 ratio and caspase activation in human gastric adenocarcinoma, AGS, cells. DNA Cell Biol, 2013. 32(2): p. 50-7.
6. Bathaie, S.Z., H. Miri, M.A. Mohagheghi, M. Mokhtari-Dizaji, A.A. Shahbazfar, and H. Hasanzadeh, Saffron Aqueous Extract Inhibits the Chemically-induced Gastric Cancer Progression in the Wistar Albino Rat. Iran J Basic Med Sci, 2013. 16(1): p. 27-38.
7. He, K., P. Si, H. Wang, U. Tahir, K. Chen, J. Xiao, et al., Crocetin induces apoptosis of BGC-823 human gastric cancer cells. Mol Med Rep, 2014. 9(2): p. 521-6.
8. Taheri, F., S.Z. Bathaie, M. Ashrafi, and E. Ghasemi, Assessment of Crocin Toxicity on the Rat Liver. mdrsjrns, 2014. 17(3): p. 67-79.
9. Mousavi, B., S.Z. Bathaie, F. Fadai, Z. Ashtari, N. Ali Beigi, S. Farhang, et al., Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed, 2015. 5(5): p. 413-9.
10. Sanjari-Pour, M., N. Faridi, P. Wang, and S.Z. Bathaie, Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy. Phytother Res, 2023.
11. Sajjadi, M. and Z. Bathaie, Comparative Study on The Preventive Effect of Saffron Carotenoids, Crocin and Crocetin, in NMU-Induced Breast Cancer in Rats. Cell J, 2017. 19(1): p. 94-101.
12. Ashrafi, M., S.Z. Bathaie, M. Taghikhani, and A.A. Moosavi-Movahedi, The effect of carotenoids obtained from saffron on histone H1 structure and H1-DNA interaction. Int J Biol Macromol, 2005. 36(4): p. 246-52.
13. Chitsazan, A., S.Z. Bathaie, M.A. Mohagheghi, and S. Banasadegh. Rat mammary tumor induced by NMU and the effect of natural carotenoids. in XXX1st Symposium on hormones and regulation: cancer cell signalling. 2006. Hostellerie du Mont Sainte Odile, Ottrott, France.
14. Shibamoto, Y. and S. Takano, Non-Surgical Definitive Treatment for Operable Breast Cancer: Current Status and Future Prospects. Cancers (Basel), 2023. 15(6).
15. Riis, M., Modern surgical treatment of breast cancer. Ann Med Surg (Lond), 2020. 56: p. 95-107.
16. Mazurakova, A., L. Koklesova, M. Samec, E. Kudela, K. Kajo, V. Skuciova, et al., Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care. Epma j, 2022. 13(2): p. 315-334.
17. Younas, M., C. Hano, N. Giglioli-Guivarc'h, and B.H. Abbasi, Mechanistic evaluation of phytochemicals in breast cancer remedy: current understanding and future perspectives. RSC Advances, 2018. 8(52): p. 29714-29744.
18. Bathaie, S.Z., N. Faridi, A. Nasimian, H. Heidarzadeh, and F. Tamanoi, How Phytochemicals Prevent Chemical Carcinogens and/or Suppress Tumor Growth? Enzymes, 2015. 37: p. 1-42.
19. Bolhassani, A., A. Khavari, and S.Z. Bathaie, Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochim Biophys Acta, 2014. 1845(1): p. 20-30.
20. Bathaie, S.Z. and S.Z. Mousavi, New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nutr, 2010. 50(8): p. 761-86.
21. Mousavi, S.H., J. Tavakkol-Afshari, A. Brook, and I. Jafari-Anarkooli, Role of caspases and Bax protein in saffron-induced apoptosis in MCF-7 cells. Food Chem Toxicol, 2009. 47(8): p. 1909-13.
22. D'Alessandro, A.M., A. Mancini, A.R. Lizzi, A. De Simone, C.E. Marroccella, G.L. Gravina, et al., Crocus sativus stigma extract and its major constituent crocin possess significant antiproliferative properties against human prostate cancer. Nutr Cancer, 2013. 65(6): p. 930-42.
23. Bathaie, S.Z., R. Hoshyar, H. Miri, and M. Sadeghizadeh, Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer. Biochem Cell Biol, 2013. 91(6): p. 397-403.
24. Dhar, A., S. Mehta, G. Dhar, K. Dhar, S. Banerjee, P. Van Veldhuizen, et al., Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. Mol Cancer Ther, 2009. 8(2): p. 315-23.
25. Magesh, V., J.P. Singh, K. Selvendiran, G. Ekambaram, and D. Sakthisekaran, Antitumour activity of crocetin in accordance to tumor incidence, antioxidant status, drug metabolizing enzymes and histopathological studies. Mol Cell Biochem, 2006. 287(1-2): p. 127-35.
26. Montalto, F.I. and F. De Amicis, Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma. Cells, 2020. 9(12).
27. Barnes, D.M. and C.E. Gillett, Cyclin D1 in breast cancer. Breast Cancer Res Treat, 1998. 52(1-3): p. 1-15.
28. Rani, R., V.K. Kansal, D. Kaushal, and S. De, Dietary intervention of cow ghee and soybean oil on expression of cell cycle and apoptosis related genes in normal and carcinogen treated rat mammary gland. Mol Biol Rep, 2011. 38(5): p. 3299-307.
29. Liu, Q., W.T. Loo, S.C. Sze, and Y. Tong, Curcumin inhibits cell proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine, 2009. 16(10): p. 916-22.
30. Jang, T.J., J.H. Park, M.Y. Cho, and J.R. Kim, Chemically induced rat mammary tumor treated with tamoxifen showed decreased expression of cyclin D1, cyclin E, and p21(Cip1). Cancer Lett, 2001. 170(2): p. 109-16.
31. Zhao, P., C.L. Luo, X.H. Wu, H.B. Hu, C.F. Lv, and H.Y. Ji, [Proliferation apoptotic influence of crocin on human bladder cancer T24 cell line]. Zhongguo Zhong Yao Za Zhi, 2008. 33(15): p. 1869-73.
32. Moon, K.Y., N-nitroso-N-methylurea and N-nitroso-N-ethylurea induce upregulation of cellular NF-kappa B activity through protein kinase C-dependent pathway in human malignant keratinocytes. Arch Pharm Res, 2010. 33(1): p. 133-9.
33. Hinz, M., D. Krappmann, A. Eichten, A. Heder, C. Scheidereit, and M. Strauss, NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol, 1999. 19(4): p. 2690-8.
34. Yang, R., L. Yang, X. Shen, W. Cheng, B. Zhao, K.H. Ali, et al., Suppression of NF-kappaB pathway by crocetin contributes to attenuation of lipopolysaccharide-induced acute lung injury in mice. Eur J Pharmacol, 2012. 674(2-3): p. 391-6.
35. Oren, M. and V. Rotter, Introduction: p53--the first twenty years. Cell Mol Life Sci, 1999. 55(1): p. 9-11.
36. Marei, H.E., A. Althani, N. Afifi, A. Hasan, T. Caceci, G. Pozzoli, et al., p53 signaling in cancer progression and therapy. Cancer Cell International, 2021. 21(1): p. 703.
37. Dotto, G.P., p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta, 2000. 1471(1): p. M43-56.
38. Jang, T.J., M.S. Kang, H. Kim, D.H. Kim, J.I. Lee, and J.R. Kim, Increased expression of cyclin D1, cyclin E and p21(Cip1) associated with decreased expression of p27(Kip1) in chemically induced rat mammary carcinogenesis. Jpn J Cancer Res, 2000. 91(12): p. 1222-32.
39. Ashrafi, M., S.Z. Bathaie, and S. Abroun, High Expression of Cyclin D1 and p21 in N-Nitroso-N-Methylurea-Induced Breast Cancer in Wistar Albino Female Rats. Cell J, 2012. 14(3): p. 193-202.
40. Crist, K.A., R.D. Fuller, B. Chaudhuri, P. Chaudhuri, and M. You, Brief communication, P53 accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors. Toxicol Pathol, 1996. 24(3): p. 370-5.
41. Jassim, M.M.A., K.H. Rasool, and M.M. Mahmood, p53, p21, and cyclin d1 protein expression patterns in patients with breast cancer. Vet World, 2021. 14(10): p. 2833-2838.
42. Zohny, S.F., A.L. Al-Malki, M.A. Zamzami, and H. Choudhry, p21(Waf1/Cip1): its paradoxical effect in the regulation of breast cancer. Breast Cancer, 2019. 26(2): p. 131-137.
43. Thor, A.D., S. Liu, D.H. Moore, 2nd, Q. Shi, and S.M. Edgerton, p(21WAF1/CIP1) expression in breast cancers: associations with p53 and outcome. Breast Cancer Res Treat, 2000. 61(1): p. 33-43.
44. Zhong, Y.J., F. Shi, X.L. Zheng, Q. Wang, L. Yang, H. Sun, et al., Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms. Acta Pharmacol Sin, 2011. 32(12): p. 1529-36.
45. Vlach, J., S. Hennecke, and B. Amati, Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J, 1997. 16(17): p. 5334-44.
46. Slingerland, J. and M. Pagano, Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol, 2000. 183(1): p. 10-7.
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| Issue | Vol 2 No 1 (2024) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/abi.v2i1.16244 | |
| Keywords | ||
| Saffron Carotenoid Cell Cycle p53 Cyclin D1 p21 p27 | ||
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How to Cite
1.
Bathaie SZ, Ashrafi M, Azizian M, Khademian N, Abroun S. Crocetin regulates cell cycle progression in N-nitroso-N-methylurea(NMU)-induced breast cancer in rat: cyclin D1 suppression, p21Cip1 and p53 induction. ABI. 2024;2(1):22-30.
