强心苷（CG）几十年来一直用于治疗心力衰竭和心律失常疾病。最近的非临床和流行病学研究结果表明，CG 具有抗肿瘤活性。因此，CGs可能被重新定位为治疗癌症的药物。详细了解 CG 的抗癌机制对于将其应用于靶向癌症类型的治疗至关重要。为了阐明与 CG 抗肿瘤作用相关的因素，我们对用 Periplocin（CG 之一）处理的人多发性骨髓瘤 AMO1 细胞进行了转录组分析。 Periplocin 显着下调 MYC (c-Myc)（一种公认的癌基因）的转录。 Periplocin 还在蛋白质水平上抑制 c-Myc 表达。在几种细胞系中也观察到了 c-Myc 的这种抑制。为了确定抑制 c-Myc 的靶蛋白，我们使用地高辛持续治疗产生了 CG 抗性 (C9) 细胞。我们证实C9细胞获得了对CGs抑制c-Myc表达和细胞增殖的抵抗力。此外，C9细胞基因组DNA测序揭示了α1-Na/K-ATPase中D128N的突变，表明了目标蛋白。这些结果表明CGs通过α1-Na/K-ATPase抑制癌细胞中c-Myc的表达，这为CGs的抗肿瘤活性提供了进一步的支持。© The Author(s) 2023。由牛津大学出版社代表出版日本生化学会会员。版权所有。

Cardiac glycosides (CGs) have been used for decades to treat heart failure and arrhythmic diseases. Recent non-clinical and epidemiological findings have suggested that CGs exhibit anti-tumor activities. Therefore, CGs may be repositioned as drugs for the treatment of cancer. A detailed understanding of the anticancer mechanisms of CGs is essential for their application to the treatment of targetable cancer types. To elucidate the factors associated with the anti-tumor effects of CGs, we performed transcriptome profiling on human multiple myeloma AMO1 cells treated with periplocin, one of CGs. Periplocin significantly down-regulated the transcription of MYC (c-Myc), a well-established oncogene. Periplocin also suppressed c-Myc expression at the protein levels. This repression of c-Myc was also observed in several cell lines. To identify target proteins for the inhibition of c-Myc, we generated CG-resistant (C9) cells using a sustained treatment with digoxin. We confirmed that C9 cells acquired resistance to the inhibition of c-Myc expression and cell proliferation by CGs. Moreover, the sequencing of genomic DNA in C9 cells revealed the mutation of D128N in α1-Na/K-ATPase, indicating the target protein. These results suggest that CGs suppress c-Myc expression in cancer cells via α1-Na/K-ATPase, which provides further support for the anti-tumor activities of CGs.© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.