Jiangsu Key Laboratory for Molecular and Medicine Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, P.R. China.
Laboratory of Molecular Biology, Jiangsu Province Hospital of TCM, Nanjing, Jiangsu 210029, P.R. China.
Mol Med Rep. 2018 Jun;17(6):7875-7885. doi: 10.3892/mmr.2018.8818. Epub 2018 Mar 28.
Traditional Chinese medicine (TCM) has the synergistic effect of the combination of a single ingredient and a monomer, and systemic and local therapeutic effects in cancer treatment, through which TCM is able to enhance the curative effect and reduce the side effects. The present study analyzed the effect of TCM‑1 (an anti‑cancer TCM) on prostate cancer (PCa) cell lines, and studied in detail the mechanism of cell death induced by TCM‑1 in vitro and in vivo. From the present results, it was identified for the first time, to the best of our knowledge, that TCM‑1 arrested the cell cycle at the G1 phase, decreased cell viability and increased nuclear rupture in a dose‑dependent manner; these effects finally resulted in apoptosis in PCa cells. At the molecular level, the data demonstrated that TCM‑1 competitively acted on epidermal growth factor receptor (EGFR) with EGF, and suppressed the auto‑phosphorylation and activity of EGFR. Inhibition of EGFR further suppressed the downstream phosphatidylinositol 3‑kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (AKT) and RAF proto‑oncogene serine/threonine‑protein kinase/extracellular signal regulated kinase signaling pathways and resulted in a decrease in the phosphorylated‑forkhead box protein O1 (at Ser256, Thr24 and Ser319) expression level, and induced cell growth inhibition and apoptosis by regulating the expression of apoptosis‑and cell cycle‑associated genes. In addition, TCM‑1 markedly inhibited the PI3K/AKT/serine/threonine‑protein kinase mTOR signaling pathway and induced cell autophagy by downregulating the phosphorylation of p70S6K and upregulating the levels of Beclin‑1 and microtubule‑associated protein light chain‑3II. In vivo, the TCM‑1‑treated group exhibited a significant decrease in tumor volume compared with the negative control group in subcutaneous xenograft nude mice by inhibiting EGFR‑associated signaling pathways. Therefore, the bio‑functions of Chinese medicine TCM‑1 in inducing PCa cell growth inhibition, autophagy and apoptosis suggested that TCM‑1 may have clinical potential for the treatment of patients with PCa.
中医（TCM）在癌症治疗中具有单一成分和单体结合的协同作用，以及全身和局部治疗效果，通过这种方式，TCM 能够增强疗效并减少副作用。本研究分析了中药 1（一种抗癌 TCM）对前列腺癌（PCa）细胞系的作用，并详细研究了 TCM-1 在体外和体内诱导细胞死亡的机制。从目前的结果来看，据我们所知，这是首次确定 TCM-1 以剂量依赖的方式将细胞周期阻滞在 G1 期，降低细胞活力并增加核破裂，最终导致 PCa 细胞凋亡。在分子水平上，数据表明 TCM-1 与 EGF 竞争作用于表皮生长因子受体（EGFR），并抑制 EGFR 的自动磷酸化和活性。EGFR 的抑制进一步抑制下游磷脂酰肌醇 3-激酶（PI3K）/RAC-α丝氨酸/苏氨酸-蛋白激酶（AKT）和 RAF 原癌基因丝氨酸/苏氨酸-蛋白激酶/细胞外信号调节激酶信号通路，导致磷酸化叉头框蛋白 O1（在 Ser256、Thr24 和 Ser319）表达水平降低，并通过调节凋亡和细胞周期相关基因的表达来诱导细胞生长抑制和凋亡。此外，TCM-1 通过下调 p70S6K 的磷酸化和上调 Beclin-1 和微管相关蛋白轻链 3II 的水平，显著抑制 PI3K/AKT/丝氨酸/苏氨酸-蛋白激酶 mTOR 信号通路并诱导细胞自噬。在体内，与阴性对照组相比，TCM-1 处理组在皮下异种移植裸鼠中通过抑制 EGFR 相关信号通路显著降低肿瘤体积。因此，中药 TCM-1 诱导 PCa 细胞生长抑制、自噬和凋亡的生物功能表明，TCM-1 可能具有治疗 PCa 患者的临床潜力。
