Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells.
Long-Term Treatment with Gadopentetic Acid or Gadodiamide Increases TRPC5 Expression and Decreases Adriamycin Nuclear Accumulation in Breast Cancer Cells.
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钆喷酸和钆双胺是顺磁性钆基造影剂（GBCA），通常用于动态对比增强磁共振成像（MRI），以监测癌症患者的疾病进展。然而，越来越多的证据表明，反复给予GBCA可能导致钆（III）阳离子在皮质骨组织、皮肤、基底神经节和小脑中蓄积，可能导致随后的Gd 3+缓慢长期放电。Gd 3+是TRPC 5通道的已知激活剂，其与乳腺癌对化疗的抗性有关。在本文中，我们发现钆喷酸（Gd-DTPA，1 mM）通过TRPC 5通道增强内向和外向电流，TRPC 5通道在HEK 293细胞中外源性表达。Gd-DTPA（1 mM）还激活了TRPC 5的Gd 3+敏感性R593 A突变体，该突变体对GPCR-Gq/11-PLC依赖性门控的敏感性降低。相反，Gd-DTPA对Gd 3+不敏感的TRPC 5突变体TRPC 5-E543 Q没有影响。人乳腺癌细胞的长期治疗（28天）（MCF-7和SK-BR-3）和阿霉素耐药MCF-7细胞（MCF-7/ADM）与Gd-DTPA（1 mM）或钆双胺（GDD，1 mM）不影响ADM的IC 50值。然而，用Gd-DTPA或GDD处理显著增加了TRPC 5的表达并减少了ADM在MCF-7和SK-BR-3细胞核中的积聚，TRPC 5的拮抗剂AC 1903（1 μM）可增加Gd-DTPA诱导的ADM在细胞核内的聚集。这些数据表明，延长GBCA治疗可能会导致乳腺癌细胞存活率增加，这是由于TRPC 5表达上调和ADM耐药性增加。我们建议，在专注于在临床上提供最佳个性化质量的医疗保健的同时，应避免在转移性乳腺癌患者中过度使用GBCA，以降低促进乳腺癌细胞耐药性的风险。
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 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 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 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 IC50 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.
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