Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Biochem Pharmacol. 2010 May 1;79(9):1242-50. doi: 10.1016/j.bcp.2009.12.014. Epub 2009 Dec 21.
Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer properties. In this study, we sought to examine the effect of Andro on signal transducer and activator of transcription 3 (STAT3) pathway and evaluate whether suppression of STAT3 activity by Andro could sensitize cancer cells to a chemotherapeutic drug doxorubicin. First, we demonstrated that Andro is able to significantly suppress both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through suppression of Janus-activated kinase (JAK)1/2 and interaction between STAT3 and gp130. For understanding the biological significance of the inhibitory effect of Andro on STAT3, we next investigated the effect of Andro on doxorubicin-induced apoptosis in human cancer cells. In our study the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to doxorubicin-induced apoptosis. Both the short-term MTT assay and the long-term colony formation assay showed that Andro dramatically promoted doxorubicin-induced cell death in cancer cells, indicating that Andro enhances the sensitivity of cancer cells to doxorubicin mainly via STAT3 suppression. These observations thus reveal a novel anticancer function of Andro and suggest a potential therapeutic strategy of using Andro in combination with chemotherapeutic agents for treatment of cancer.
穿心莲内酯（Andro）是从传统草药穿心莲中分离得到的一种二萜内酯，具有很强的抗炎和抗癌特性。在这项研究中，我们试图研究 Andro 对信号转导和转录激活因子 3（STAT3）途径的影响，并评估 Andro 对 STAT3 活性的抑制是否能使癌细胞对化疗药物阿霉素敏感。首先，我们证明 Andro 能够显著抑制癌细胞中组成性激活和 IL-6 诱导的 STAT3 磷酸化以及随后的核转位。这种抑制作用是通过抑制 Janus 激活激酶（JAK）1/2 和 STAT3 与 gp130 之间的相互作用来实现的。为了了解 Andro 对 STAT3 的抑制作用的生物学意义，我们接下来研究了 Andro 对人癌细胞中阿霉素诱导的细胞凋亡的影响。在我们的研究中，STAT3 的组成性激活水平与癌细胞对阿霉素诱导的细胞凋亡的抵抗能力有关。短期 MTT 测定和长期集落形成测定均表明，Andro 显著促进了阿霉素诱导的癌细胞死亡，表明 Andro 主要通过抑制 STAT3 来增强癌细胞对阿霉素的敏感性。这些观察结果揭示了 Andro 的一种新的抗癌功能，并提示了一种潜在的治疗策略，即用 Andro 与化疗药物联合治疗癌症。
