Synergistic Effect of Layered Double Hydroxides Nanodosage Form to Induce Apoptosis and Ferroptosis in Breast Cancer

Abstract

Background

Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.

Methods

In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer.

Results

The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe²⁺ in cells through the release of Fe³⁺, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis.

Conclusion

In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis−apoptosis combined anticancer therapy.

Keywords:

• layered double hydroxides
• apoptosis
• ferroptosis
• simvastatin
• breast cancer

Ethics Approval

The animal study was reviewed and approved by the Experimental Animal Management and Ethics Committee and Ethics Committee of Bengbu Medical University, Anhui Province, China, Ethics Number: [2023] No. 537.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by the Nature Science Research Project of Anhui Province2108085MH294), the University Synergy Innovation Program of Anhui Province (GXXT-2022-064), the Postgraduate Research Innovation Program of Bengbu Medical College (Byycx22006) and the Anhui province Undergraduate Training Programs for Innovation and Entrepreneurship (s202310367041).