A mitochondria-targeting and G-quadruplex structure-binding ligand inducing calcium overload and ferroptosis in human...

Area of Science:

• Mitochondrial dysfunction and cancer therapy
• Targeted drug delivery for cancer
• Ferroptosis induction mechanisms

Background:

• Mitochondria-targeting ligands offer a promising anticancer strategy by regulating mitochondrial calcium overload and ferroptosis.
• Developing effective mitochondria-targeting ligands that induce these processes remains a significant challenge in cancer research.

Purpose of the Study:

• To investigate the anticancer potential of a novel mitochondria-targeting ligand, BYB, with G-quadruplex binding capabilities.
• To demonstrate BYB's ability to induce mitochondrial calcium overload and ferroptosis in cancer cells.
• To evaluate the in vitro and in vivo anticancer efficacy of BYB.

Main Methods:

• Utilized cell viability assays, live-cell imaging, western blotting, and immunofluorescence to study cellular functions.
• Assessed molecular mechanisms including cell cycle arrest, apoptosis, mitochondrial metabolism, and DNA damage (Comet assay).
• Conducted pharmacokinetic studies in rats and evaluated in vivo antitumor activity in a cervical cancer xenograft mouse model.

Main Results:

• BYB inhibited mitochondrial DNA replication and transcription, leading to mitochondrial dysfunction and calcium overload.
• BYB treatment downregulated respiratory chain complexes, dysregulated respiratory function, induced mitophagy, and increased mitochondrial reactive oxygen species (mtROS).
• Mitochondrial calcium overload activated the cGAS-STING pathway, resulting in autophagy-dependent ferroptosis and over 60% tumor weight reduction in vivo.

Conclusions:

• BYB effectively targets mitochondria and mtDNA G-quadruplexes, inducing mitochondrial calcium overload and ferroptosis.
• BYB demonstrated significant in vivo antitumor efficacy with low toxicity, highlighting its potential as a lead compound.
• BYB shows promise for chemical biology and drug discovery as a mitochondria-targeting anticancer agent.