Recoding the Cancer Epigenome by Intervening in Metabolism and Iron Homeostasis with Mitochondria‐Targeted Rhenium(I) Complexes

Abstract

The development and malignancy of cancer cells are closely related to the changes of the epigenome.I nt his work, am itochondria-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,D NA,a nd RNA. As ac onsequence, DFX-Re3 affects the events related to apoptosis,R NA polymerases,a nd 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 an ew approachf or the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.

Transition-metal complexes of N,N′-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide: synthesis, characterization, biological activities, ADMET and drug-likeness analysis

“…White Powder, mp 235 -236 °C; 1 (40), 449 (9), 447 (10), 359 (18), 357 (20), 216 (15), 215 (100), 214 (15), 213 (99), 183 (3.9), 181 (4), 158 (2.5), 156 (3), 155 (25), 143 (2), 134 (50), 117 (2), 107 (9), 76 (8)…”

“…Metal complexes have been used for a considerable time as pharmaceutical agents, especially in the chemotherapy against cancer [1,2]. More recently, large interest has grown in the use of transition metal complexes [3,6].…”

Potent Ruthenium–Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish

“…Mitochondrial damage and/or dysfunction leads to impairment of mitochondrial membrane potential (ΔΨ m ). 55,56 To this end, a fluorescent ΔΨ m indicator, namely, 5,5,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) dye, in combination with flow cytometry was used to measure ΔΨ m in 1-treated HeLa cells. In the case of healthy and functional mitochondria with intact ΔΨ m , the JC-1 dye accumulates in mitochondria as aggregates and is emitted in the red channel, whereas in case of unhealthy mitochondria with depleted ΔΨ m , the JC-1 dye accumulates as monomers inside mitochondria and is emitted in the green channel.…”

Metal-based anticancer agents as immunogenic cell death inducers: the past, present, and future

“…On a similar note, intervening iron homeostasis pathway can also facilitate or augment immunogenic cell death. 66 Recent studies with a rhenium complex conjugated to an iron chelator deferasirox 67 showed upregulation of CRT translocation in MDA-MB-231 triple negative breast cancer cells. This is indicative of ICD induction in vitro ; however, further experiments with similar complexes need to be carried out to confirm the rationale.…”