Pharmacologic ascorbate resistant pancreatic cancer demonstrates enhanced metastatic potential

Area of Science:

• Oncology
• Biochemistry
• Cancer Biology

Background:

• Pharmacological ascorbate (P-AscH), a high-dose vitamin C pro-drug, generates hydrogen peroxide and is explored as neoadjuvant therapy for pancreatic ductal adenocarcinoma (PDAC).
• Phase II trials show P-AscH efficacy and safety, but patient response varies, indicating treatment resistance in a subset of PDAC patients.

Purpose of the Study:

• To characterize PDAC cells exhibiting resistance to P-AscH.
• To determine if P-AscH resistance is associated with enhanced metastatic potential in PDAC.

Main Methods:

• Characterization of P-AscH-resistant PDAC cell lines.
• Assessment of hydrogen peroxide detoxification, redox metabolism, and cell cycle regulation.
• Transcriptomic analysis to identify gene expression patterns.
• In vivo studies evaluating invasive potential, tumor colonization, and circulating tumor cell abundance.

Main Results:

• P-AscH resistance increased H₂O₂ detoxification and altered redox metabolism and cell cycle regulation, with distinct mechanisms across cell lines.
• Transcriptomic analysis revealed enrichment of epithelial-to-mesenchymal transition (EMT) gene expression patterns in resistant cells.
• P-AscH-resistant cells exhibited increased invasiveness, aggressive tumor colonization, and higher circulating tumor cell counts in vivo.

Conclusions:

• Resistance to P-AscH in PDAC is linked to enhanced metastatic capabilities.
• Acquired resistance to oxidative stress may promote PDAC metastasis and contribute to treatment unresponsiveness.