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Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells

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 GB...

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Published in:Cells (Basel, Switzerland) Switzerland), 2023-05, Vol.12 (9), p.1304
Main Authors: Zhang, Weiheng, Wang, Mengyuan, Lv, Weizhen, White, Fletcher A, Chen, Xingjuan, Obukhov, Alexander G
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Obukhov, Alexander G
description 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 Gd . Gd is a known activator of the TRPC5 channel that is implicated in breast cancer's resistance to chemotherapy. Herein, we found that gadopentetic acid (Gd-DTPA, 1 mM) potentiated the inward and outward currents through TRPC5 channels, which were exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd -sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-G -PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7 and SK-BR-3) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect the IC values of ADM. However, treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 and SK-BR-3 cells, promoting the survival of these two breast cancer cells in the presence of ADM. The antagonist of TRPC5, AC1903 (1 μM), increased ADM nuclear accumulation induced by Gd-DTPA-treatment. These data indicate that prolonged GBCA treatment may lead to increased breast cancer cell survival owing to the upregulation of TRPC5 expression and the increased ADM resistance. We propose that while focusing on providing medical care of the best personalized quality in the clinic, excessive administration of GBCAs should be avoided in patients with metastatic breast cancer to reduce the risk of promoting breast cancer cell drug resistance.
doi_str_mv 10.3390/cells12091304
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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 Gd . Gd is a known activator of the TRPC5 channel that is implicated in breast cancer's resistance to chemotherapy. Herein, we found that gadopentetic acid (Gd-DTPA, 1 mM) potentiated the inward and outward currents through TRPC5 channels, which were exogenously expressed in HEK293 cells. Gd-DTPA (1 mM) also activated the Gd -sensitive R593A mutant of TRPC5, which exhibits a reduced sensitivity to GPCR-G -PLC dependent gating. Conversely, Gd-DTPA had no effect on TRPC5-E543Q, a Gd insensitive TRPC5 mutant. Long-term treatment (28 days) of human breast cancer cells (MCF-7 and SK-BR-3) and adriamycin-resistant MCF-7 cells (MCF-7/ADM) with Gd-DTPA (1 mM) or gadodiamide (GDD, 1 mM) did not affect the IC values of ADM. However, treatment with Gd-DTPA or GDD significantly increased TRPC5 expression and decreased the accumulation of ADM in the nuclei of MCF-7 and SK-BR-3 cells, promoting the survival of these two breast cancer cells in the presence of ADM. The antagonist of TRPC5, AC1903 (1 μM), increased ADM nuclear accumulation induced by Gd-DTPA-treatment. These data indicate that prolonged GBCA treatment may lead to increased breast cancer cell survival owing to the upregulation of TRPC5 expression and the increased ADM resistance. We propose that while focusing on providing medical care of the best personalized quality in the clinic, excessive administration of GBCAs should be avoided in patients with metastatic breast cancer to reduce the risk of promoting breast cancer cell drug resistance.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>37174704</pmid><doi>10.3390/cells12091304</doi><orcidid>https://orcid.org/0000-0001-8820-5120</orcidid><orcidid>https://orcid.org/0000-0002-7380-8399</orcidid><orcidid>https://orcid.org/0000-0002-3862-6004</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 2073-4409
ispartof Cells (Basel, Switzerland), 2023-05, Vol.12 (9), p.1304
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subjects Antibodies
Basal ganglia
Breast cancer
Breast Neoplasms - drug therapy
Cancer
Cell culture
Cell survival
Cerebellum
Channel gating
Chemotherapy
chemotherapy resistance
Contrast agents
Contrast media
Contrast Media - pharmacology
Cortical bone
Dosage and administration
Doxorubicin
Doxorubicin - pharmacology
Doxorubicin - therapeutic use
Drug interactions
Drug resistance
Drug therapy
Female
G protein-coupled receptors
Gadolinium
Gadolinium - metabolism
Gadolinium - pharmacology
Gadolinium DTPA - pharmacology
Gadopentetate dimeglumine
GBCAs
Glucose
Glycoproteins
Health aspects
HEK293 Cells
Histamine
Humans
Magnetic resonance imaging
Metastases
Metastasis
Mutants
Oncology, Experimental
Organometallic Compounds
Patients
Penicillin
Thermal cycling
TRPC Cation Channels - metabolism
TRPC5
title Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells
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