Synthical logo
Your space
Activity icon
Favorites icon
Account icon
From chemRxiv
Sichuan University

A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction in vitro and in vivo independently of ROS induction

G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. Here, we first demonstrated that the G4-binding platinum(II) complex, Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy significantly induces deletion, copy number reduction and transcription inhibition of mt DNA, and it hinders the translation of mt proteins. Functional study shows that Pt-ttpy induces a potent mt dysfunction indicated by a high reduction of mt membrane potential, oxygen consumption rate and ATP synthesis, as well as toxic mt morphology switching, but without reactive oxygen species (ROS) induction. Mechanistic study by RNA-seq, Chip-seq and CUT-RUN shows Pt-ttpy impairs most nuclear-encoded mt ribosome genes’ transcription initiation through dampening the recruiting of TAF1 and NELFB to their promoter, which are highly enriched in G4 forming sequences. In vivo studies on a A2780 tumor xenograft mouse model suggest Pt-ttpy’s efficient anti-tumor effects, causing substantial disruption in mt genome function, while exhibiting less side effects compared to cisplatin. Overall, this study presents the first evidence that a G4-binding platinum(II) complex can harm cancer cell mitochondria potently without inducing ROS activity, potentially reducing side effects that shows promise in developing safer and effective platinum-based G4-binding molecules in cancer therapy.
Upvote icon
Published on November 16, 2023
Copy BibTeX
Cross iconSummary
There is no AI-powered summary yet, because we do not have a budget to generate summaries for all articles.
1. Buy subscription
We will thank you for helping thousands of people to save their time at the top of the generated summary.
If you buy our subscription, you will be able to summarize multiple articles.
Pay $8
≈10 summaries
Pay $32
≈60 summaries
2. Share on socials
If this article gets to top-5 in trends, we'll summarize it for free.
Copy link