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Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids.

ABSTRACT: Pancreatic ductal adenocarcinoma is a hard-to-treat, deadly malignancy. Traditional treatments, such as surgery, radiation and chemotherapy, unfortunately are still not able to significantly improve long-term survival. Three-dimensional (3D) cell cultures might be a platform to study new drug types in a highly reproducible, resource-saving model within a relevant pathophysiological cellular microenvironment. We used a 3D culture of human pancreatic ductal adenocarcinoma cell lines to investigate a potential new treatment approach using superparamagnetic iron oxide nanoparticles (SPIONs) as a drug delivery system for mitoxantrone (MTO), a chemotherapeutic agent. We established a PaCa DD183 cell line and generated PANC-1^{SMAD4 (-/-)} cells by using the CRISPR-Cas9 system, differing in a prognostically relevant mutation in the TGF-β pathway. Afterwards, we formed spheroids using PaCa DD183, PANC-1 and PANC-1^{SMAD4 (-/-)} cells, and analyzed the uptake and cytotoxic effect of free MTO and MTO-loaded SPIONs by microscopy and flow cytometry. MTO and SPION-MTO-induced cell death in all tumor spheroids in a dose-dependent manner. Interestingly, spheroids with a SMAD4 mutation showed an increased uptake of MTO and SPION-MTO, while at the same time being more resistant to the cytotoxic effects of the chemotherapeutic agents. MTO-loaded SPIONs, with their ability for magnetic drug targeting, could be a future approach for treating pancreatic ductal adenocarcinomas.

SUBMITTER: Dinter J

PROVIDER: S-EPMC10096321 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids.

Dinter Jonas J Friedrich Ralf P RP Yang Hai H Pilarsky Christian C Mangge Harald H Pöttler Marina M Janko Christina C Alexiou Christoph C Lyer Stefan S

Materials (Basel, Switzerland) 20230406 7

Pancreatic ductal adenocarcinoma is a hard-to-treat, deadly malignancy. Traditional treatments, such as surgery, radiation and chemotherapy, unfortunately are still not able to significantly improve long-term survival. Three-dimensional (3D) cell cultures might be a platform to study new drug types in a highly reproducible, resource-saving model within a relevant pathophysiological cellular microenvironment. We used a 3D culture of human pancreatic ductal adenocarcinoma cell lines to investigate ...[more]

PMID: 37049199

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Project description:The present study aimed to synthesize iron oxide nanoparticles loaded with quinine and alkaloids-rich Cinchona officinalis (Peruvian bark) stem bark extract, and further evaluate their cytotoxic effect and apoptosis mechanisms in MCF-7 breast cancer cells. Nanoparticles were prepared by biological reduction of iron oxide with Cinchona officinalis extract, using the green synthesis method. The nanoparticles were characterized by XRD, FT-IR, and UV-vis spectroscopy and transmission electron microscopy (TEM). In vitro cytotoxicity analyses of Cinchona officinalis extract, ferrous oxide, and Cinchona officinalis extract-loaded iron oxide nanoparticles (CO-NPs) were carried out using the MTT test for 24 h and 48 h. We found that CO-NPs reduced the MCF-7 cell viability with IC50 values of 16.2 and 9 µg/mL in 24 h and 48 h, respectively. In addition, CO-NPs were tested with normal hMSCs to determine their toxicity, and we did not find noticeable cytotoxicity. Confocal fluorescent microscopy revealed that CO-NPs efficiently increased the nuclear condensation and chromatin damage in propidium iodide staining; meanwhile, there was decreased mitochondrial membrane potential in CO-NPs-treated MCF-7 cells. In addition, AO-EB staining confirmed the late apoptotic and apoptotic morphology of cancer cells. Further gene expression analysis confirmed that the upregulation of tumor suppressors, Cdkn1A, Prb, and p53 was significantly increased, and inflammatory traits such as TNF-α and Nf-κb were increased in cancer cells treated with CO-NPs. Apoptotic stimulators such as Bax and caspase-3 expression were highly significantly increased, while mdm-2 and Bcl-2 were significantly decreased. Overall, the enhanced cytotoxic potential of the Cinchona officianlis stem bark extract loaded CO-NPs versus free Cinchona officianlis extract might be due to the functional stabilization of bioactive compounds, such as alkaloids, quinine, flavonoids, phenolics, etc., into the iron oxide, providing bioavailability and internalization of cinchona metabolites intracellularly.

Dataset Information

Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids.

Publications

Mitoxantrone and Mitoxantrone-Loaded Iron Oxide Nanoparticles Induce Cell Death in Human Pancreatic Ductal Adenocarcinoma Cell Spheroids.

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