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Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat

  • Authors:
    • Hellen Röttgen
    • Lana Theurer
    • Teresa Peccerella
    • Ketaki Sandu
    • Johanna Weiss
    • Jürgen Burhenne
    • John P. Neoptolemos
    • Beate Köberle
    • Dirk Theile
  • View Affiliations / Copyright

    Affiliations: Internal Medicine IX‑Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University, Medical Faculty Heidelberg, Heidelberg University Hospital, D‑69120 Heidelberg, Germany, Department of Food Chemistry and Toxicology, Karlsruhe Institute of Technology, D‑76131 Karlsruhe, Germany, Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Medical Faculty Heidelberg, Heidelberg University Hospital, D‑69120 Heidelberg, Germany
    Copyright: © Röttgen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 22
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    Published online on: November 19, 2025
       https://doi.org/10.3892/or.2025.9027
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) resistance to oxaliplatin is associated with diminished drug uptake and a poor molecular apoptotic response; however, the relative contribution of each of these modes of resistance remains unclear. Accordingly, PDAC cell lines (AsPC‑1 and BxPC‑3) and human patient‑derived organoids (hPDOs; h08 and h19) were assessed in the present study, with proliferation assays, atomic absorption spectroscopy‑based quantification of intracellular oxaliplatin, luminogenic caspase 3/7 assays, PCR array‑based transcriptomic analysis and RNA sequencing performed to scrutinize the oxaliplatin resistance phenotype. Notably, AsPC‑1 cells [half maximal inhibitory concentration (IC50), 88.8±45 µM were 4.2‑fold more oxaliplatin resistant than BxPC‑3 cells (IC50, 21±0.7 µM; P=0.02)]. In addition, when normalized to intracellular platinum levels, AsPC‑1 cells remained 2.5‑fold more resistant than BxPC‑3 (the fold difference was decreased by 40% from 4.2‑fold to 2.5‑fold; P=0.21). In hPDOs, resistant h19 took up oxaliplatin 22% less efficiently than sensitive h08, and the nominal resistance difference was 3.5‑fold, and it remained at 2.8‑fold after controlling for drug accumulation (the fold difference was decreased by 20% from 3.5‑fold to 2.8‑fold; P=0.34). These findings indicated that diminished drug uptake non‑significantly contributed to oxaliplatin resistance, which was in agreement with the rather minor differences in drug transporter expression levels (including ATP7A and ATP7B). Furthermore, when challenged with identical intracellular oxaliplatin levels, AsPC‑1 cells exhibited delayed caspase 3/7 activity initiation, weaker induction of pro‑apoptotic genes BBC3 (1.7‑fold vs. 5‑fold) and PMAIP (2.5‑fold vs. 6‑fold), but stronger enhancement of anti‑apoptotic Jun expression (7‑fold vs. 3‑fold) than BxPC‑3 cells. Taken together, oxaliplatin resistance in PDAC models may be highly linked to a poor apoptotic response, whereas drug uptake seems to be of minor relevance.
View Figures

Figure 1

Anti-proliferative pharmacodynamics
of oxaliplatin. Concentration-dependent proliferation inhibition in
(A and B) AsPC-1 and BxPC-3 cells, and (C and D) h08 and h19 hPDOs,
in response to (A and C) nominal extracellular exposure
concentrations or (B and D) resulting total intracellular
concentrations. Data are presented as the mean ± SD of four (cell
lines) or three (hPDOs) independent experiments with technical
octuplets each. Data were fitted to a sigmoidal dose-response curve
with variable slope of the log-transformed data. *P<0.05. hPDOs,
human patient-derived organoids.

Figure 2

Anti-proliferative pharmacodynamics
of the control drug cisplatin. Concentration-dependent
proliferation inhibition in AsPC-1 and BxPC-3, in response to (A)
nominal extracellular exposure concentrations or (B) resulting
total intracellular concentrations. Data are presented as the mean
± SD of four independent experiments with technical octuplets each.
Data were fitted to a sigmoidal dose-response curve with variable
slope of the log-transformed data. *P<0.05.

Figure 3

Uptake characteristics of platinum
drugs. (A) Uptake of oxaliplatin or cisplatin into AsPC-1 and
BxPC-3 cells, or (B) oxaliplatin uptake into h08 and h19 human
patient-derived organoids. Data are presented as the mean ± SD of
four independent experiments. Data were fitted to a linear
regression, including the 95% confidence interval values for h08
and h19, which are presented as dotted lines.

Figure 4

mRNA expression levels of major
platinum drug transporters in untreated pancreatic ductal
adenocarcinoma models. (A) Relative mRNA expression levels in
AsPC-1 cells, normalized to the levels in BxPC-3 cells. Data are
presented as the mean ± SD of three independent experiments with
technical duplicates each (PCR runs). (B) mRNA expression levels in
h19 and h08 human patient-derived organoids. The number of
transcripts per million are shown, extracted from RNA sequencing
data.

Figure 5

Caspase 3/7 activity upon similar
platinum drug challenge. (A) Validation of similar total
intracellular platinum concentrations in AsPC-1 and BxPC-3 cells
after treatment with respective drug concentrations. Data are
presented as the mean ± SD of four to five independent experiments.
The black line represents the mean total intracellular platinum
concentration of the four groups with the SD (gray area). (B)
Kinetics of caspase 3/7 activity in cells after treatment with
respective extracellular concentrations leading to similar total
intracellular platinum concentrations. Data are presented as the
mean ± SD of three to six independent experiments, normalized to
the untreated control at the respective time point.

Figure 6

Treatment-related gene expression
alterations. Heatmap of gene expression profiling of AsPC-1 and
BxPC-3 cells after treatment with oxaliplatin or cisplatin
concentrations that led to identical total intracellular platinum
concentrations each. The log2 mean values of three independent
experiments (with technical duplicates each) are shown, normalized
to the untreated control set to 0. Missing values are indicated by
white boxes.

Figure 7

Treatment-related significant gene
expression alterations. Statistically significant log2-fold changes
of expression levels after exposure of AsPC-1 or BxPC-3 cells to
(A) oxaliplatin or (B) cisplatin, which led to identical total
intracellular platinum concentrations each. The log2 mean values ±
SD of three independent experiments (with technical duplicates
each) are shown, normalized to the untreated control set to 0.
*P<0.01, **P<0.001, ***P<0.0001 indicates a significant
difference of gene expression between AsPC-1 and BxPC-3 and is
placed above the cell line with higher mRNA expression.

Figure 8

Relative gene expression levels in
human patient-derived organoids. Genes with (A) 2-fold higher or
(B) 2-fold lower expression levels in h19 (red) compared with h08
(black). Log2 gene expression is shown as transcripts per
million.
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Copy and paste a formatted citation
Spandidos Publications style
Röttgen H, Theurer L, Peccerella T, Sandu K, Weiss J, Burhenne J, Neoptolemos JP, Köberle B and Theile D: Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat. Oncol Rep 55: 22, 2026.
APA
Röttgen, H., Theurer, L., Peccerella, T., Sandu, K., Weiss, J., Burhenne, J. ... Theile, D. (2026). Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat. Oncology Reports, 55, 22. https://doi.org/10.3892/or.2025.9027
MLA
Röttgen, H., Theurer, L., Peccerella, T., Sandu, K., Weiss, J., Burhenne, J., Neoptolemos, J. P., Köberle, B., Theile, D."Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat". Oncology Reports 55.1 (2026): 22.
Chicago
Röttgen, H., Theurer, L., Peccerella, T., Sandu, K., Weiss, J., Burhenne, J., Neoptolemos, J. P., Köberle, B., Theile, D."Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat". Oncology Reports 55, no. 1 (2026): 22. https://doi.org/10.3892/or.2025.9027
Copy and paste a formatted citation
x
Spandidos Publications style
Röttgen H, Theurer L, Peccerella T, Sandu K, Weiss J, Burhenne J, Neoptolemos JP, Köberle B and Theile D: Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat. Oncol Rep 55: 22, 2026.
APA
Röttgen, H., Theurer, L., Peccerella, T., Sandu, K., Weiss, J., Burhenne, J. ... Theile, D. (2026). Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat. Oncology Reports, 55, 22. https://doi.org/10.3892/or.2025.9027
MLA
Röttgen, H., Theurer, L., Peccerella, T., Sandu, K., Weiss, J., Burhenne, J., Neoptolemos, J. P., Köberle, B., Theile, D."Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat". Oncology Reports 55.1 (2026): 22.
Chicago
Röttgen, H., Theurer, L., Peccerella, T., Sandu, K., Weiss, J., Burhenne, J., Neoptolemos, J. P., Köberle, B., Theile, D."Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat". Oncology Reports 55, no. 1 (2026): 22. https://doi.org/10.3892/or.2025.9027
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