Recoding the Cancer Epigenome by Intervening in Metabolism and Iron Homeostasis with Mitochondria-Targeted Rhenium(I) Complexes.
Zheng-Yin PanCai-Ping TanLu-Si RaoHang ZhangYue ZhengLiang HaoLiang-Nian JiZong-Wan MaoPublished in: Angewandte Chemie (International ed. in English) (2020)
The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Keyphrases
- cell death
- dna methylation
- cell cycle arrest
- genome wide
- gene expression
- papillary thyroid
- oxidative stress
- iron deficiency
- reactive oxygen species
- cancer therapy
- signaling pathway
- squamous cell
- endoplasmic reticulum
- anti inflammatory
- squamous cell carcinoma
- cell proliferation
- lymph node metastasis
- drug delivery
- binding protein