Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Br J Cancer. 2011 Feb 1;104(3):437-40. doi: 10.1038/sj.bjc.6606065. Epub 2011 Jan 18.
Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs.
To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-κB (NF-κB) inactivation in the chemosensitising effect of monoHER.
MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-κB activation.
These results suggest that reduction of doxorubicin-induced NF-κB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells.
尽管治疗方法有所进步，但转移性软组织肉瘤（STS）患者的预后仍然非常差。最近一项评估半合成类黄酮 7-单-O-（β-羟乙基）芦丁（单 HER）对多柔比星诱导的心脏毒性的保护作用的临床二期研究结果表明，单 HER 增强了多柔比星在 STS 中的抗肿瘤活性。
为了从分子水平解释这一意外发现，我们研究了单 HER 对多柔比星细胞毒性的影响，以及谷胱甘肽（GSH）耗竭和核因子-κB（NF-κB）失活在单 HER 化学增敏作用中的潜在作用。
单 HER 增强了人脂肪肉瘤细胞系 WLS-160 中多柔比星的抗肿瘤活性。此外，与单独使用多柔比星相比，单 HER 与多柔比星联合使用在 WLS-160 细胞中诱导了更多的细胞凋亡。单 HER 并未降低细胞内 GSH 水平。另一方面，单 HER 预处理可显著降低多柔比星诱导的 NF-κB 激活。
这些结果表明，单 HER 通过降低多柔比星诱导的 NF-κB 激活，使癌细胞对细胞凋亡敏感，从而参与了单 HER 在人脂肪肉瘤细胞中的化学增敏作用。
