Background/Objectives: Doxorubicin (DOX) is commonly used as a chemotherapeutic agent for the treatment of breast cancer. Nonetheless, its systemic delivery via intravenous injection and toxicity towards healthy tissues commonly result in a broad range of detrimental side effects. Breast cancer severity was previously shown to be correlated with TRPC1 channel expression that conferred upon it enhanced vulnerability to pulsed electromagnetic field (PEMF) therapy. PEMF therapy was also previously shown to enhance breast cancer cell vulnerability to DOXin vitroandin vivothat correlated with TRPC1 expression and mitochondrial respiratory rates.Methods: DOX uptake was assessed by measuring its innate autofluorescence within murine 4T1 or human MCF7 breast cancer cells following magnetic exposure. Cellular vulnerability to doxorubicin uptake was assessed by monitoring mitochondrial activity and cellular DNA content.Results: Here, we demonstrate that 10 min of PEMF exposure could augment DOX uptake into 4T1 and MCF7 breast cancer cells. DOX uptake could be increased by TRPC1 overexpression, whereas inhibiting the activity of TRPC1 channels with SKF-96356 or genetic knockdown, precluded DOX uptake. PEMF exposure enhances DOX-mediated killing of breast cancer cells, reducing the IC50value of DOX by half, whereas muscle cells, representative of collateral tissues, were less sensitive to PEMF-enhanced DOX-mediated cytotoxicity. Vesicular loading of DOX correlated with TRPC1 expression.Conclusions: This study presents a novel TRPC1-mediated mechanism through which PEMF therapy may enhance DOX cytotoxicity in breast cancer cells, paving the way for the development of localized non-invasive PEMF platforms to improve cancer outcomes with lower systemic levels of DOX.
背景/目的：阿霉素（DOX）是治疗乳腺癌的常用化疗药物。然而，其通过静脉注射的全身给药方式以及对健康组织的毒性常导致一系列有害副作用。先前研究表明，乳腺癌的严重程度与TRPC1通道表达相关，该表达增强了肿瘤对脉冲电磁场（PEMF）治疗的敏感性。既往研究亦证实，PEMF治疗能增强乳腺癌细胞在体外和体内对DOX的敏感性，这种效应与TRPC1表达及线粒体呼吸速率相关。 方法：通过测量小鼠4T1或人源MCF7乳腺癌细胞在磁场暴露后DOX自身荧光强度评估其摄取情况。通过监测线粒体活性和细胞DNA含量评估细胞对阿霉素摄取的敏感性。 结果：本研究发现10分钟PEMF暴露可促进4T1和MCF7乳腺癌细胞对DOX的摄取。TRPC1过表达可增强DOX摄取，而使用SKF-96356抑制TRPC1通道活性或基因敲低则会阻断该摄取过程。PEMF暴露增强了DOX介导的乳腺癌细胞杀伤作用，使DOX的IC50值降低一半，而作为旁侧组织代表的肌肉细胞对PEMF增强的DOX介导细胞毒性较不敏感。DOX的囊泡装载与TRPC1表达呈正相关。 结论：本研究揭示了一种新型TRPC1介导机制，通过该机制PEMF治疗可增强DOX对乳腺癌细胞的细胞毒性，为开发局部非侵入性PEMF平台奠定了基础，该平台可在降低全身DOX剂量的同时提升癌症治疗效果。
肿瘤(癌症)患者之家