Reversible chemoresistance of pancreatic cancer grown as spheroids

Better <i>in vitro</i> models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

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Publication Details

Journal
Journal of Chemotherapy
Published
2024-09-16
DOI
https://doi.org/10.1080/1120009x.2024.2402177
Citations
1
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
0.28

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article

Reversible chemoresistance of pancreatic cancer grown as spheroids

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1 citations
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Reversible chemoresistance of pancreatic cancer grown as spheroids

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article en
1 citations

Abstract

Better <i>in vitro</i> models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

Journal of ChemotherapyVol. 37(6)
Johns Hopkins University (US), Occupational Cancer Research Centre (CA)
Johns Hopkins University, Rolfe Pancreatic Cancer Foundation, National Institutes of Health
Zero hunger
Openalex Percentile: Top 36%
Pancreatic and Hepatic Oncology Research
0.28
DOIOpen Access PDFOpenAlex
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