crocin and Neoplasm-Metastasis

To determine the anti-metastatic potential of combinations of two bioactive carotenoids of saffron, crocin and crocetin, on 4T1 breast cancer and on a mice model of TNBC, and assess the effect of the most potent combination on the Wnt/β-catenin pathway.. The effects of the carotenoid combinations on the viability of 4T1 cells were determined by MTT assay. The effects of the nontoxic doses on migration, mobility, invasion and adhesion to ECM were examined by scratch assay, Transwell/Matrigel-coated Transwell chamber and adhesion assay respectively. Tumors were inoculated by injecting mice with 4T1 cells. The weights and survival rates of the mice and tumor sizes were monitored. Histological analysis of the tissues was conducted. The expression levels of Wnt/β-catenin pathway genes were measured by Real-time PCR and western blotting.. Treatment of 4T1 cells with combination doses inhibited viability in a dose-dependent manner. The nontoxic combinations significantly inhibited migration, cell mobility and invasion, also attenuating adhesion to ECM. The combination therapy mice possessed more weight, higher survival rates and smaller tumors. Histological examination detected remarkably fewer metastatic foci in their livers and lungs. It was also demonstrated that the combinations exerted anti-metastatic effects by disturbing the Wnt/β-catenin target genes in the liver and tumors.. Our findings propose a carotenoid combination as an alternative potent herbal treatment for TNBC, which lacks the adverse effects associated with either chemotherapeutic agents or herb-chemotherapeutic drugs.

Topics: Animals; Carotenoids; Cell Line; Cell Proliferation; Herbal Medicine; Humans; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Triple Negative Breast Neoplasms; Vitamin A

Crocus sativus L. (saffron) has been used as a spice and as a medicine for the past four thousand years. Recently, saffron has been well documented to possess anticancer effects on primary tumors. However studies of its antimetastatic potential are lacking. The present study is a comparative investigation of the antimetastatic effects of saffron carotenoids, crocin and crocetin, on triple negative metastatic breast cancer cells (4T1) and their effects on the Wnt/β-catenin pathway. It was found that treatment of 4T1 cells with crocin and crocetin resulted in the inhibition of viability in a dose-dependent manner. Scratch and Transwell chamber assays showed that the nontoxic doses of crocin and crocetin significantly inhibited migration, cell mobility, and invasion, also attenuating adhesion to extracellular matrix. Crocin downregulated mRNA expression of FZD7, NEDD9, VIM, and VEGF-α genes and upregulated E-CAD. Crocin and crocetin exhibited comparable anti-invasion properties on 4T1 cells. However, crocin and crocetin exerted more pronounced antimigration and antiadhesion potency, respectively. Furthermore, we showed that the antimetastatic effects of crocin can occur through interfering with the Wnt/β-catenin pathway.

Topics: Animals; beta Catenin; Breast Neoplasms; Carotenoids; Cell Adhesion; Cell Movement; Crocus; Female; Humans; Mice; Neoplasm Metastasis; Plant Extracts; Tumor Cells, Cultured; Vitamin A; Wnt Signaling Pathway

Triple-negative breast cancer (TNBC) is the most metastatic subtype of breast cancer and cannot be controlled with any standard-of-care therapy. However, various studies have recommended medicinal plants as complementary treatments for cancer. In particular, crocin, the main bioactive carotenoid of saffron, has exhibited anticancer effects on primary tumors. This research, for the first time, investigated the antimetastatic potency of crocin on murine model of metastatic TNBC and its effect on the Wnt/β-catenin pathway. To induce tumors, 4T1 cells were injected to female BALB/c mice. Measurement of biochemical markers showed nontoxicity of crocin. The crocin-treated mice possessed more weight, higher survival rates, and smaller tumors. Histological examination detected no metastatic deposits in their livers and lungs. Also, downregulation of the expression of Wnt/β-catenin target genes in tumors and lungs was observed compared to the untreated group. Our findings suggest crocin as a promising complementary antimetastatic herbal medicine for treatment of TNBC.

Topics: Animals; Antineoplastic Agents; Carotenoids; Cell Line, Tumor; Female; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Triple Negative Breast Neoplasms; Wnt Signaling Pathway