Long-term treatment with gadopentetic acid or gadodiamide increases TRPC5 expression and decreases adriamycin nuclear accumulation in breast cancer cells

Abstract

Abstract Gadopentetic acid and gadodiamide are paramagnetic gadolinium-based contrast agents (GBCAs) that are routinely used for dynamic contrast-enhanced magnetic resonance imaging (MRI) to monitor disease progression in cancer patients. However, growing evidence indicates that repeated administration of GBCAs may lead to gadolinium (III) cation accumulation in the cortical bone tissue, skin, basal ganglia, and cerebellum, potentially leading to a subsequent slow long-term discharge of Gd3+. Gd3+ is a known activator of the TRPC5 channel which is implicated in breast cancer resistance to chemotherapy. Here we found that gadopentetic acid (Gd-DTPA, 1 mM) enhanced the inward and outward currents through TRPC5 exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd3+ sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-Gq/11-PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd3+ insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect cell survival in the presence of ADM. However, the treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 cells, increasing the risk of the breast cancer cell chemoresistance. The antagonist of TRPC5, AC1903 (1 µM), reversed the Gd-DTPA-treatment mediated changes in ADM nuclear accumulation. We propose that clinically, repeated administration of GBCAs should be minimized in breast cancer patients to reduce the risk of drug resistance.