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

Abstract

Siyan Pang,1,2 Chenchen Geng,1,2 Zihan Fan,2 Min Hou,1,3 Huilan Mao,1,2 Shuang Tao,1,4 Jing Wang,1,4 Yulun Wu,1,2 Ke Wei,1,4 Yunhao Li,1,2 Liuyang Yan,1,2 Qingling Yang,1,4,5 Changjie Chen,1,4,5 Wenrui Wang1,2,6 1Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical University, Anhui, People’s Republic of China; 2Department of Life Sciences, Bengbu Medical University, Anhui, People’s Republic of China; 3School of Basic Courses, Bengbu Medical University, Anhui, People’s Republic of China; 4Clinical Testing and Diagnose Experimental Center, Bengbu Medical University, Anhui, People’s Republic of China; 5Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui, People’s Republic of China; 6Department of Biotechnology, Bengbu Medical University, Anhui, People’s Republic of ChinaCorrespondence: Wenrui Wang; Changjie Chen, Anhui Province Key Laboratory of Cancer Translational Medicine, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, Anhui, 233030, People’s Republic of China, Email [email protected]; [email protected]: 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

Keywords

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