Carboranyl-1,8-naphthalimide intercalators induce lysosomal membrane permeabilization and ferroptosis in cancer cell lines

Abstract

The synthesis of carborane-1,8-naphthalimide conjugates and evaluation of their DNA-binding ability and anticancer activity were performed. A series of 4-carboranyl-3-nitro-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, were synthesised via amidation and reductive amination reactions, and their calf thymus DNA (ct-DNA)-binding properties were investigated using circular dichroism, UV–vis spectroscopy, and thermal denaturation. Results showed that conjugates 34 – 37 interacted very strongly with ct-DNA (Δ T m = 10.00–13.00 °C), indicating their ability to intercalate with DNA, but did not inhibit the activity of topoisomerase II. The conjugates inhibited the cell growth of the HepG2 cancer cell line in vitro . The same compounds caused the G2M phase arrest. Cell lines treated with these conjugates showed an increase in reactive oxygen species, glutathione, and Fe 2+ levels, lipid peroxidation, and mitochondrial membrane potential relative to controls, indicating the involvement of ferroptosis. Furthermore, these conjugates caused lysosomal membrane permeabilization in HepG2 cells but not in MRC-5 cells.

Black Phosphorus Quantum Dots Effectively and Safely Treat Glaucoma as a Promising Anti-Ferroptosis Nano-drug

“…Morphological changes include reduced mitochondrial size, increased membrane density, and fragmentation or disappearance of the mitochondrial crest 13,63 . Ferroptosis is involved in the pathogenesis of various clinical diseases, e.g., tumors, neurodegenerative diseases, and ischemic reperfusion injury diseases, including glaucoma [8][9][10][11] . Direct intervention for iron, such as the use of iron chelators to remove abnormally elevated iron, can inhibit RGC ferroptosis under glaucoma conditions and protect visual function 11,64 .…”

“…Ferroptosis, an iron-regulated cell death form, differs from conventional cell death forms due to its distinct morphological, biochemical, and genetic features. It plays a signi cant role in various pathophysiological processes and holds promise as a therapeutic target for human diseases, including cancer, neurodegenerative diseases, and ischemic organ damage [8][9][10] . Our recent study found that ferroptosis is involved in RGC loss induced by ph-IOP in glaucoma 11 .…”

The role of sphingosine-1-phosphate in the development and progression of Parkinson’s disease

“…The S1P signaling pathway plays a crucial role in regulating cell migration. S1P is a bioactive lipid that acts as a potent extracellular signaling molecule, binding to specific cell surface receptors and initiating intracellular signaling cascades ( Rykowski et al, 2023 ). Especially, it is a complex process that plays a vital role in multiple physiological function, such as regeneration, angiogenesis, cell mediated immune responses, as well as tumor progression ( Chi et al, 2022 ).…”