Aconitine Impedes Cell Motility in MDA-MB-231 Breast Cancer Cells: A Potential Therapeutic Avenue

Abstract

Purpose: Aconitine, a potent alkaloid from Aconitum plants, has shown promising anticancer properties. The aim of the study is to investigate the effects of aconitine on lateral migration, and matrix metalloproteinase (MMP) activity in MDA-MB-231 triple-negative breast cancer cells. Material and Methods: A WST-1 viability assay was conducted to determine the effect of aconitine on the viability of MDA-MB-231 cells. Following treatment with non-cytotoxic doses of aconitine, lateral migration was evaluated through wound healing assays. Additionally, gelatin zymography was conducted to analyze MMP-2 and MMP-9 activity and secretion levels. Results: Aconitine concentrations up to 200 μM did not significantly affect cell viability for up to 72 hours, whereas higher doses (400-600 μM) reduced viability in a time-dependent manner. Aconitine at 200 μM showed a trend towards decreased lateral motility, with a significant reduction at 9 hours post-treatment. Gelatin zymography revealed no alterations in MMP-2 and MMP-9 activity or secretion levels following aconitine treatment. Conclusion: Aconitine demonstrates limited efficacy in modulating the migratory capacity of MDA-MB-231 cells and does not affect gelatinase activity. Further investigation into underlying mechanisms is necessary, potentially leading to novel therapeutic strategies for triple-negative breast cancer.

Keywords

• Aconitine
• Cell Motility
• Matrix metalloproteinases
• Triple Negative Breast cancer

Project Number

This study was not supported by any financial resources.

Ethical Statement

Ethical approval was obtained from the Health Sciences Research Ethics Committee of Izmir University of Economics, Izmir, Turkey (Ethics Committee No: B.30.2.İEÜSB.0.05.05-20-317; date: 08/12/2024).

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74(3):229–263.
2. Gao Y, Fan H, Nie A, et al. Aconitine: A review of its pharmacokinetics, pharmacology, toxicology and detoxification. J Ethnopharmacol 2022;293:115270.
3. Xiang G, Xing N, Wang S, Zhang Y. Antitumor effects and potential mechanisms of aconitine based on preclinical studies: an updated systematic review and meta-analysis. Front Pharmacol 2023;14:1172939.
4. Mustafa S, Koran S, AlOmair L. Insights Into the Role of Matrix Metalloproteinases in Cancer and its Various Therapeutic Aspects: A Review. Front Mol Biosci 2022;9:896099.
5. Conlon GA, Murray GI. Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol 2019;247(5):629–640.
6. Işlekel H, Oktay G, Terzi C, Canda AE, Füzün M, Küpelioǧlu A. Matrix metalloproteinase-9,-3 and tissue inhibitor of matrix metalloproteinase-1 in colorectal cancer: Relationship to clinicopathological variables. Cell Biochem Funct 2007;25(4):433-441.
7. Keles D, Arslan B, Terzi C, et al. Expression and activity levels of matrix metalloproteinase-7 and in situ localization of caseinolytic activity in colorectal cancer. Clin Biochem 2014;47(13–14):1265–1271.
8. Keleş D, Sipahi M, İnanç-Sürer Ş, Djamgoz MB, Oktay G. Tetracaine downregulates matrix metalloproteinase activity and inhibits invasiveness of strongly metastatic MDA-MB-231 human breast cancer cells. Chem Biol Interact 2023;385:110730.

9. Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal 2003;15(2):151–159.
10. Wright SN. Comparison of aconitine-modified human heart (hH1) and rat skeletal (μ1) muscle Na+ channels: an important role for external Na+ ions. J Physiol 2002;538(Pt 3):759-771.
11. Kunze DL, Lacerda AE, Wilson DL, Brown AM. Cardiac Na currents and the inactivating, reopening, and waiting properties of single cardiac Na channels. J Gen Physiol 1985;86(5):691–719.
12. Ji BL, Xia LP, Zhou FX, Mao GZ, Xu LX. Aconitine induces cell apoptosis in human pancreatic cancer via NF-κB signaling pathway. Eur Rev Med Pharmacol Sci 2016;20:4955-4964.
13. Du J, Lu X, Long Z, et al. In Vitro and in Vivo Anticancer Activity of Aconitine on Melanoma Cell Line B16. Mol 2013:18(1):757–767.
14. Qi X, Wang L, Wang H, Yang L, Li X, Wang L. Aconitine inhibits the proliferation of hepatocellular carcinoma by inducing apoptosis. Int J Clin Exp Pathol. 2018;11(11): 5278–5289.
15. Xiong HS, Jiang C, Gao R, Chen LH. Regulatory effects and mechanism of aconitine on proliferation,invasion and migration of hepatoma carcinoma cell MHCC97. Chinese J Immunol 2018;34(5):688–692.
16. Fraser SP, Salvador V, Manning EA, et al. Contribution of functional voltage-gated Na+ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: I. Lateral motility. J Cell Physiol 2003;195(3):479–487.
17. Feng HT, Zhao WW, Lu JJ, Wang YT, Chen XP. Hypaconitine inhibits TGF-β1-induced epithelial–mesenchymal transition and suppresses adhesion, migration, and invasion of lung cancer A549 cells. Chin J Nat Med 2017;15(6):427-435.
18. Guo BF, Liu S, Ye YY, Han XH. Inhibitory effects of osthole, psoralen and aconitine on invasive activities of breast cancer MDA-MB-231BO cell line and the mechanisms. Zhong Xi Yi Jie He Xue Bao 2011;9(10):1110–1117.
19. Wang X, Lin Y, Zheng Y. Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration. Mol Med Rep 2020;22(3):2318-2328.