School of Graduates, Beijing University of Chinese Medicine, Beijing 100029, China; Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China.
Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China.
J Ethnopharmacol. 2021 Feb 10;266:113430. doi: 10.1016/j.jep.2020.113430. Epub 2020 Oct 2.
Astragalus mongholicus, Solanum nigrum Linn, Lotus plumule, Ligusticum are widely used traditional herbal medicines for cancer treatment in China. They were typical drugs selected from Gubenyiliu II and series of formula (GYII), which were developed on the foundation of YIQIHUOXUEJIEDU theory. In the present study, four active ingredients (Astragaloside IV, α-solanine, neferine, and 2,3,5,6-tetramethylpyrazine) derived from medicines above were applied in combination as SANT.
Triple-negative breast cancer (TNBC) is a serious threat to women's health worldwide. Heparanase (HPSE) is often up-regulated in breast cancer with the properties of facilitating tumorigenesis and influencing the autophagy process in cancer cells. This study aimed at evaluating the anti-tumor potential of SANT in treating HPSE related TNBC both in-vitro and in-vivo.
In this study, we explored the correlation between HPSE expression and survival of breast cancer patients in databases. We performed MTS, trans-well and wound scratch assays to assess the impact of SANT on cell proliferation and migration. Confocal microscopy observation and western blots were applied to verify the autophagy flux induced by SANT. Mice models were employed to evaluate the efficacy and safety of SANT in-vivo by tumor weights and volumes or serum index, respectively. To analyze the underlying mechanisms of SANT, we conducted human autophagy PCR array and angiogenesis proteome profiler on tumor tissues.
Patients with elevated HPSE expression were associated with a poor outcome in both RFS (P = 1.7e-12) and OS (P = 0.00016). SANT administration significantly inhibited cancer cells' proliferation and migration, enhanced autophagy flux, and slightly reduced the active form of HPSE in-vitro. SANT also suppressed tumor growth and angiogenesis in-vivo. Human autophagy PCR array results indicated that SANT increased the ATG16L1, ATG9B, ATG4D gene expressions while decreased TMEM74 and TNF gene expressions.Angiogenesis proteome profiler results showed SANT reduced protein level of HB-EGF, thrombospondin-2, amphiregulin, leptin, IGFBP-9, EGF, coagulation factor III, and MMP-9 (pro and active form) in tumor, raised the protein expression of serpin E1 and platelet factor 4.
These findings indicated that herbal compounds SANT may be a promising candidate in anti-cancer drug discovery. It also provides novel strategies for using natural compounds to achieve optimized effect.
蒙古黄芪、龙葵、莲心、川芎等在中国被广泛用于癌症治疗的传统草药。它们是从 Gubenyiliu II 和系列配方（GYII）中选择的典型药物，这些药物是在“益气活血解毒”理论的基础上开发的。在本研究中，四种来自上述药物的活性成分（黄芪甲苷 IV、α-茄碱、小檗碱和 2,3,5,6-四甲基吡嗪）被组合成 SANT。
三阴性乳腺癌（TNBC）是全世界女性健康的严重威胁。肝素酶（HPSE）在乳腺癌中常被上调，具有促进肿瘤发生和影响癌细胞自噬过程的特性。本研究旨在评估 SANT 在体外和体内治疗与 HPSE 相关的 TNBC 的抗肿瘤潜力。
在这项研究中，我们在数据库中探索了 HPSE 表达与乳腺癌患者生存之间的相关性。我们进行 MTS、trans-well 和划痕实验，以评估 SANT 对细胞增殖和迁移的影响。共聚焦显微镜观察和 Western blot 用于验证 SANT 诱导的自噬通量。通过肿瘤重量和体积或血清指标，分别在小鼠模型中评估 SANT 的体内疗效和安全性。为了分析 SANT 的潜在机制，我们对肿瘤组织进行了人类自噬 PCR 阵列和血管生成蛋白组分析。
HPSE 表达升高的患者在 RFS（P=1.7e-12）和 OS（P=0.00016）方面的预后均较差。SANT 给药显著抑制了癌细胞的增殖和迁移，增强了自噬通量，并且在体外略微降低了 HPSE 的活性形式。SANT 还抑制了体内肿瘤生长和血管生成。人类自噬 PCR 阵列结果表明，SANT 增加了 ATG16L1、ATG9B 和 ATG4D 基因的表达，同时降低了 TMEM74 和 TNF 基因的表达。血管生成蛋白组分析结果表明，SANT 降低了肿瘤中 HB-EGF、血小板反应蛋白-2、双调蛋白、瘦素、IGFBP-9、EGF、凝血因子 III 和 MMP-9（原和活性形式）的蛋白水平，提高了 serpin E1 和血小板因子 4 的蛋白表达。
这些发现表明，草药化合物 SANT 可能是一种有前途的抗癌药物发现候选物。它还为使用天然化合物实现最佳效果提供了新的策略。
