Investigation of the Putative Relationship Between Copper Transport and the Anticancer Activity of Cisplatin in Ductal Pancreatic Adenocarcinoma

TL;DR

This study explores how copper transport affects cisplatin's effectiveness in treating pancreatic cancer, suggesting new ways to improve chemotherapy.

Contribution

The study introduces novel adjuvant strategies for PDAC treatment by modulating copper transport mechanisms.

Findings

Drugs modulating copper transport enhanced cisplatin's anticancer activity in pancreatic cancer cells.

Elesclomol was the most effective compound in elevating intracellular copper and cisplatin levels.

Copper transporter inhibition reduced efflux and increased chemotherapy efficacy in vitro.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with a severe stromal reaction mediated by pancreatic stellate cells (PSCs), leading to increased resistance to chemotherapy and radiotherapy. Following a repurposing concept, this preclinical study investigates the potential of approved drugs, known to be modulators of cellular copper transport, in combination with cisplatin for therapeutic approaches in PDAC. Two major strategies were pursued: (i) inhibiting copper transporters ATP7A and B with tranilast (TR) and omeprazole (OM) to block the cellular copper and, potentially, also cisplatin efflux, and (ii) using the chelator elesclomol (ES) to elevate intracellular copper and cisplatin levels. Human cell lines PanC-1 (PDAC), HPaSteC (PSC), and their co-culture, as well as the hepatocellular carcinoma cell line HepG2 as a reference model, were used. In addition to an analysis of the expression of copper transport proteins, the dynamics of cellular copper uptake and transport were monitored using a [64Cu]CuCl2 radiotracer approach. In vitro, all drugs enhanced cellular copper uptake and/or reduced copper efflux. Moreover, all drugs contributed to the enhanced cellular anticancer activity of cisplatin, with ES being the most effective compound. The results suggest that the targeted modulation of copper transport mechanisms may offer novel adjuvant approaches for the treatment of PDAC.

Figures