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Diethyldithiocarbamate-Cu4O3 nanocomplex induced mitochondrial and telomerase dysfunction in non-small cell lung
Marwa M Abu-Serie1, María A Blasco2
1Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Egypt.
Background:
Targeting cancer stem cells (CSCs)-mediated aggressive features of non-small cell lung cancer (NSCLC) is a promising anticancer approach. This can be accomplished via suppressing critical mediators, such as functional mitochondria, aldehyde dehydrogenase (ALDH)1A, and telomere protectors (telomerase reverse transcriptase (TERT) and telomere repeat binding factor (TRF)1).
Materials & Methods:
Copper nanocomplexes (diethyldithiocarbamate (DE)-Cu4O3 nanoparticles (NPs) and DE-Cu NPs) were prepared using the simplest green chemistry method and assessed for inducing mitochondrial dysfunction-dependent non-apoptotic pathway (cuproptosis) and repressing CSC markers.
Results:
DE-Cu4O3 NPs had higher growth inhibition for NSCLC (A549, H520, and H1299) spheroids than DE-Cu NPs. DE-Cu4O3 NPs had higher uptake rate and prooxidant effect resulting in lower mitochondrial membrane potential and mitochondrial DNA copy number, as well as stronger inhibition of telomerase and ALDH1A than DE-Cu NPs. This caused dramatic redox imbalance and lowering AKT pathway (activator of telomere stabilizers and stemness)-mediated repression of TERT and TRF1 protein levels as well as phosphorylated NF-κB subunit (p65) led to collapsing telomeres, as evidenced by downregulating TERT regulators and confocal microscopy. In animal study, this active nanocomplex revealed powerful and selective therapeutic tumor-targeting effects, with no evidence of toxicity to healthy tissues.
Conclusion:
DE-Cu4O3 nanocomplex is deemed as promising nanomedicine for NSCLC.
Insights
Copper nanocomplexes effectively target non-small cell lung cancer stem cells by inducing cuproptosis and repressing key stemness markers. This promising nanomedicine demonstrates potent tumor-targeting effects with no observed toxicity in animal studies.
Area of Science:
- Nanomedicine
- Cancer Research
- Materials Science
Background:
- Non-small cell lung cancer (NSCLC) aggressiveness is driven by cancer stem cells (CSCs).
- Targeting CSCs requires suppressing mediators like mitochondria, aldehyde dehydrogenase (ALDH)1A, and telomere protectors (telomerase reverse transcriptase (TERT) and telomere repeat binding factor (TRF)1).
Purpose of the Study:
- To develop and evaluate copper nanocomplexes for targeting CSC-mediated NSCLC.
- To assess the efficacy of diethyldithiocarbamate (DE)-Cu4O3 nanoparticles (NPs) in inducing cuproptosis and repressing CSC markers.
Main Methods:
- Green chemistry synthesis of DE-Cu4O3 NPs and DE-Cu NPs.
- Assessment of NP uptake, prooxidant effects, and mitochondrial dysfunction in NSCLC cell lines.
- Evaluation of inhibition of telomerase, ALDH1A, AKT pathway, and TERT/TRF1 protein levels.
- In vivo studies in animal models to determine therapeutic effects and toxicity.
Main Results:
- DE-Cu4O3 NPs exhibited superior growth inhibition of NSCLC spheroids compared to DE-Cu NPs.
- DE-Cu4O3 NPs showed higher uptake, induced significant mitochondrial dysfunction (reduced membrane potential and DNA copy number), and strongly inhibited telomerase and ALDH1A.
- Redox imbalance and suppressed AKT pathway led to decreased TERT and TRF1, collapsing telomeres.
- Animal studies confirmed potent, selective tumor-targeting effects of DE-Cu4O3 nanocomplexes with no observed toxicity.
Conclusions:
- DE-Cu4O3 nanocomplex demonstrates significant potential as a nanomedicine for NSCLC treatment.
- The mechanism involves cuproptosis induction and suppression of CSC markers and telomere maintenance pathways.
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