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Small molecular weight polyfluoroalkyl phosphonates induce ROS-mediated cytotoxicity in glioblastoma cells: a
Patryk Wołodkiewicz1,2, Michał Juszczak1, Paweł Tokarz3
1Faculty of Biology and Environmental Protection, Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland.
Abstract:
Glioblastoma (GBM) is an aggressive brain tumour with limited treatment options and poor patient survival, largely due to the blood-brain barrier (BBB) restricting effective drug delivery. In this study, we focused on two small molecular weight polyfluoroalkyl phosphonates, ZOT5-1-Me and ZOT5-1-Et, designed to permeate the BBB. Comprehensive in vitro analyses using U-87 MG cells and a panel of glioma cell lines revealed that both compounds exhibit potent cytostatic and cytotoxic activities. Mechanistically, they induce reactive oxygen species (ROS) production, triggering both intrinsic and extrinsic apoptotic pathways via caspase-dependent and caspase-independent mechanisms. Additionally, ZOT5-1-Me and ZOT5-1-Et induced DNA damage, including single-strand breaks and alkali-labile sites. Notably, ZOT5-1-Me also caused significant DNA double-strand breaks and impaired DNA repair. Furthermore, both compounds exhibited antiproliferative effects by inducing cell cycle arrest in the S phase and activating p53-p21 signalling pathway. Pre-treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated these cytotoxic effects, underscoring the central role of oxidative stress in mediating the compounds' antitumour activity. Collectively, our findings suggest that these polyfluoroalkyl phosphonates represent promising ROS-modulating chemotherapeutic candidates with unique mechanisms of action that may complement existing GBM treatment strategies.
Insights
Two novel polyfluoroalkyl phosphonates show promise for treating glioblastoma (GBM) by inducing cancer cell death through oxidative stress and DNA damage, potentially overcoming the blood-brain barrier for better drug delivery.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Glioblastoma (GBM) presents significant therapeutic challenges due to its aggressive nature and the blood-brain barrier (BBB) limiting drug efficacy.
- Existing treatments for GBM have limited success, necessitating the development of novel therapeutic agents.
Purpose of the Study:
- To evaluate the anti-cancer potential of two small molecule polyfluoroalkyl phosphonates, ZOT5-1-Me and ZOT5-1-Et, against glioblastoma.
- To elucidate the mechanisms of action, including their ability to cross the BBB and induce cancer cell death.
Main Methods:
- In vitro studies using U-87 MG and other glioma cell lines.
- Assessment of cytostatic and cytotoxic effects, apoptosis induction, DNA damage, cell cycle arrest, and signaling pathway activation.
- Evaluation of reactive oxygen species (ROS) generation and the role of oxidative stress.
Main Results:
- Both ZOT5-1-Me and ZOT5-1-Et demonstrated potent cytostatic and cytotoxic activities against glioma cells.
- Compounds induced apoptosis via intrinsic and extrinsic pathways, caused DNA damage (single-strand breaks, alkali-labile sites, and double-strand breaks by ZOT5-1-Me), and S-phase cell cycle arrest.
- ROS production was identified as a key mediator of the compounds' anti-tumour effects, as confirmed by N-acetyl-L-cysteine (NAC) pre-treatment.
Conclusions:
- Polyfluoroalkyl phosphonates ZOT5-1-Me and ZOT5-1-Et are effective ROS-modulating agents with potential for glioblastoma therapy.
- These compounds exhibit unique mechanisms of action, including BBB penetration and induction of oxidative stress and DNA damage.
- They represent promising candidates for novel glioblastoma chemotherapeutic strategies, potentially complementing existing treatments.
