Kim Ji Young, Cho Youngkwan, Oh Eunhye, Lee Nahyun, An Hyunsook, Sung Daeil, Cho Tae-Min, Seo Jae Hong
Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea; Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
Cancer Lett. 2016 Aug 28;379(1):39-48. doi: 10.1016/j.canlet.2016.05.026. Epub 2016 May 26.
HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers.
已知HER2阳性乳腺肿瘤含有癌干细胞样细胞群体，并与侵袭性肿瘤表型和不良临床结果相关。双硫仑（DSF）是一种抗酒精中毒药物，已知在铜（Cu）存在的情况下，它会在许多癌细胞类型中引发细胞毒性。本研究的目的是研究DSF/Cu诱导细胞凋亡的作用机制及其对HER2阳性乳腺癌体外和体内癌干细胞特性的影响。DSF/Cu处理诱导细胞凋亡，这与HER2、截短的p95HER2、磷酸化HER2、HER3、磷酸化HER3和磷酸化Akt水平的显著降低以及p27核积累有关。这伴随着癌干细胞样群体的根除，同时醛脱氢酶1（ALDH1）活性和乳腺球形成受到抑制。给予DSF导致肿瘤生长显著减少，细胞凋亡增加，以及HER2细胞内结构域（ICD）和ALDH1A1下调。我们的结果表明，DSF/Cu通过抑制HER2/Akt信号传导诱导细胞凋亡并消除癌干细胞样细胞，这表明DSF可能对HER2阳性癌症的治疗具有潜在疗效。
