Effect of Crocin on Cell Cycle Regulators in N-Nitroso-N-Methylurea-Induced Breast Cancer in Rats

Abstract

We previously showed the anticancer effect of crocin, a saffron carotenoid, in both breast and gastric cancers in animal models, but its mechanism of action is not clearly known, yet. In this study, the effect of crocin on cell cycle regulators is investigated. Female Wistar Albino rats were divided into two groups, with or without N-nitroso-N-methylurea (NMU) injection. After tumor formation, each group of rats was divided into two subgroups, receiving crocin or vehicle only. After 5 weeks, the rats were sacrificed and the tumors were retained for pathologic investigation and determination of the parameters. Before crocin treatment, the tumor volumes were 13.27±3.77 and 12.37±1.88, but at the end of the experiment, they were 23.66±8.82 and 11.91±2.27 in the control and crocin-treated groups, respectively. Pathologic investigation indicated the adenocarcinoma induction by NMU. Reverse transcription-polymerase chain reaction and Western blot analysis showed overexpression of cyclin D1 and p21(Cip1) in the NMU-induced breast tumors; however, the expression of both of them suppressed by crocin treatment. The previous studies indicated that crocin induces apoptosis in tumor tissue. In this study, we show that it also suppresses tumor growth and induces cell cycle arrest by downregulation of cyclin D1. In addition, crocin suppressed p21(Cip1) in a p53-dependent manner.

Crocin synergistically enhances the antiproliferative activity of 5‐flurouracil through Wnt/PI3K pathway in a mouse model of colitis‐associated colorectal cancer

“…In agreement with this study, blocking Wnt activity can be considered as a strategy to reverse the drug-sensitivity of CD133-positive cells to 5-FU. 49 Zhao et al 50 have also reported the potential activity of crocin in the downregulation of cyclin D1 in bladder cancer. 48 In a study on N-nitroso-Nmethylurea-induced breast cancer in rats, crocin induced cell cycle arrest via suppression of cyclin D1.…”

Therapeutic effects of Crocin in autoimmune diseases: A review

“…One of the main activities by Crocin is a change in the expression of genes related in the redox system of cells such as GST, GPx, CAT, and SOD. In addition to changes in gene expression levels, interactions with cellular enzymes including SOD proteins or peroxidase have also been reported to induce the antioxidant activity of Crocin . Another mechanism underlying the antioxidant activity of Crocin is the alteration of the stress marker genes in the ER system.…”

“…In addition to changes in gene expression levels, interactions with cellular enzymes including SOD proteins or peroxidase have also been reported to induce the antioxidant activity of Crocin. 10,13,29,61 Another mechanism underlying the antioxidant activity of Crocin is the alteration of the stress marker genes in the ER system. Genes related to ER oxidative stress markers, whose expression is modulated by the Crocin are XBP-1/s, BiP, PERK, and CHOP.…”

A comprehensive review on anticancer mechanisms of the main carotenoid of saffron, crocin

“…Interestingly, crocin exhibited no significant effect on the growth of noncancerous cells . Moreover, several in‐vivo studies have showed the anticancer effect of crocin on various cancers such as breast and gastric tumours in animal models …”

“…Changes in the level of mRNA expression and enzyme activity of the genes in the cellular redox system including glutathione S‐transferase (GST), glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) are considered as remarkable mechanisms. Rather than expression changes of the genes, various mechanisms of action were reported to be related with the antioxidant effect of saffron extracts such as interaction with enzymes (SOD proteins, peroxidases) or signal transduction compartments of free radicals in the monocytes and direct suppression of ROS through interaction of a wide variety of proteins with antioxidant compounds . Moreover, endoplasmic reticulum (ER) is closely linked to oxidative stress status of the cells; the transcriptional level changes of the ER stress markers XBP‐1/s, BiP, PERK and CHOP are responsible for many stress‐induced diseases including cancer.…”