Abstract
The cause of death in most breast cancer patients is disease metastasis and the occurrence of multidrug resistance (MDR). Ornithine decarboxylase (ODC), which is involved into multiple pathways, is closely related to carcinogenesis and development. Ursolic acid (UA), a natural triterpenoid compound, has been shown to reverse the MDR characteristics of tumor cells. However, the effect of UA on the invasion and metastasis of tumor cells with MDR is not known. Therefore, we investigated the effects of UA on invasion and metastasis, ODC-related polyamine metabolism, and MAPK-Erk-VEGF/MMP-9 signaling pathways in a doxorubicin-resistant breast cancer cell (MCF-7/ADR) model. The obtained results showed that UA significantly inhibited the adhesion and migration of MCF-7/ADR cells, and had higher affinities with key active cavity residues of ODC compared to the known inhibitor di-fluoro-methyl-ornithine (DFMO). UA could downregulate ODC, phosphorylated Erk (P-Erk), VEGF, and matrix metalloproteinase-9 (MMP-9) activity. Meanwhile, UA significantly reduced the content of metabolites of the polyamine metabolism. Furthermore, UA increased the intracellular accumulation of Dox in MCF-7/ADR cells. Taken together, UA can inhibit against tumor progression during the treatment of breast cancer with Dox, and possibly modulate the Erk-VEGF/MMP-9 signaling pathways and polyamine metabolism by targeting ODC to exert these effects.
Highlights
Breast cancer has the highest incidence and mortality rate among women worldwide, with an estimated 2,261,419 new cases and 684,996 deaths in 2020 according to the data obtained from the GLOBOCAN 2020 online database [1]
We investigated the effects of Ursolic acid (UA) on the invasion and metastasis ability of MCF-7/ADR cells
UA could inhibit the expression of Ornithine decarboxylase (ODC) and vascular endothelial growth factor (VEGF), the phosphorylation of Erk1/2, the activity of matrix metalloproteinase-9 (MMP-9), and polyamine metabolism, eventually resulting in the suppression of metastasis in MCF-7/ADR cells
Summary
Breast cancer has the highest incidence and mortality rate among women worldwide, with an estimated 2,261,419 new cases and 684,996 deaths in 2020 according to the data obtained from the GLOBOCAN 2020 online database [1]. The emergence of multidrug resistance (MDR) severely reduces the efficacy of antitumor drugs, further leading to a decline in survival rate. MDR is closely related with rapid recurrence and metastasis in cancer patients. Increased attention has been focused on the finding of drugs with high activity and low toxicity for targeting tumor MDR, metastasis and recurrence. In this regard, phytocompounds, proven as a powerful chemopreventive and chemotherapeutic strategy in various cancers, including breast cancer, could be considered as a powerful resource for finding potential anticancer drugs [4]. Targeting polyamine metabolism has been suggested to be a promising strategy for overcoming drug resistance. Polyamine metabolism is associated with breast cancer metastasis
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