A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome.

BACKGROUND: 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. METHODS: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. RESULTS: 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 induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. CONCLUSION: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.

Far beyond anti-angiogenesis: Benefits for anti-basicFGF therapy in cancer.

Basic FGF (bFGF) was discovered as a typical inducer of angiogenesis and has already been studied for 3 decades. Recent evidence indicates that bFGF plays different roles and controls signaling pathways that participate in the hallmarks of cancer, underscoring bFGF an appealing target for anti-cancer therapy. However, the early clinical trials designed to block bFGF signaling showed safety without satisfiable benefits for cancer patients. In this review, we firstly discuss bFGF's canonical signaling pathways and later review newly identified bFGF's functions that contribute to the cancer hallmarks besides its typical role in angiogenesis. After, we summarize the role of bFGF as a therapeutic target in response to different cancer therapies including radiotherapy, chemotherapy, targeted therapy, immunotherapy, and highlight the difficulties we must solve regarding the design of drugs targeting specifically bFGF. We also emphasize the need, especially for natural bFGF traps, to deepen their molecular mechanisms of action considering the specific context of cancer with different FGFR status, as well as the urgence of stratifying patients for both anti-bFGF first line and second line anti-cancer therapy. Finally, a perspective on potential feed-forward oncogenic signaling pathways mediated by bFGF is made. We discuss the importance of developing additional robust biomarkers to select patients who will benefit from bFGF-targeted therapy, as well as the rationale of developing combinatory therapies targeting either bFGF and/or its intracellular (co)effectors. This would ultimately provide novel therapeutic strategies to fight cancer.