Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China; The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China.
The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China.
Chin J Nat Med. 2021 Feb;19(2):143-152. doi: 10.1016/S1875-5364(21)60015-8.
Drug resistance is a major obstacle in the development of effective colorectal cancer (CRC) therapy. Our study aimed to explore the reversal abilities of Jiedu Sangen decoction (JSD) on the 5-fluorouracil (5-FU) resistance and its underlying molecular mechanisms. Expression changes in HIF-1 of CRC tissues were firstly revealed by bioinformatics analysis. Afterwards, cell viabilities of JSD and 5-FU treatments on 5-FU resistant human colon cancer cells (HCT-8/5-FU) were determined. Expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT)/p-AKT, hypoxia-inducible factor 1 (HIF-1α), as well as glycolysis related proteins such as L-lactate dehydrogenase A (LDHA), Glucose transporter type 1 (Glut1), Hexokinase 2 (HKII), and cysteinyl aspartate specific proteinase (Caspase) family members in HCT-8/5-FU cells, HIF-1α silenced HCT-8/5-FU cells and tumor tissues were detected by western blotting. HIF-1α was found over expressed in CRC tissues according to public available datasets in Oncomine. Growth inhibition rates of HCT-8/5-FU cells were increased along with the increase of JSD concentrations. JSD caused down-regulated HIF-1α, PI3K, AKT/p-AKT, HKII and Glut1, as well as up-regulated Caspase3 and Caspase9 in HCT-8/5-FU cells and tumor tissues. In HIF-1α silenced HCT-8/5-FU cells, synergistic group showed significantly reduced expression levels of PI3K, AKT, p-AKT. Additionally, up-regulated expressions of Caspase6 and Caspase7 were observed. JSD combined with 5-FU also exhibited obvious inhibitory efficiency on tumor growth in vivo. JSD may reverse 5-FU resistance by suppressing glycolysis via PI3K/AKT/HIF-1α signaling pathway, thereby inhibiting glycolysis and induce apoptosis to enhance anti-tumor activity.
耐药性是开发有效结直肠癌（CRC）治疗方法的主要障碍。我们的研究旨在探索解毒散积汤（JSD）对 5-氟尿嘧啶（5-FU）耐药性的逆转能力及其潜在的分子机制。首先通过生物信息学分析揭示了 CRC 组织中 HIF-1 的表达变化。随后，测定 JSD 和 5-FU 处理对 5-FU 耐药人结肠癌细胞（HCT-8/5-FU）的细胞活力。通过 Western blot 检测 HCT-8/5-FU 细胞、HIF-1α 沉默 HCT-8/5-FU 细胞和肿瘤组织中磷酸肌醇 3-激酶（PI3K）、蛋白激酶 B（AKT）/p-AKT、缺氧诱导因子 1（HIF-1α）以及糖酵解相关蛋白如 L-乳酸脱氢酶 A（LDHA）、葡萄糖转运蛋白 1（Glut1）、己糖激酶 2（HKII）和半胱天冬氨酸特异性蛋白酶（Caspase）家族成员的表达。根据 Oncomine 中公开的可用数据集，发现 HIF-1α 在 CRC 组织中过度表达。随着 JSD 浓度的增加，HCT-8/5-FU 细胞的生长抑制率增加。JSD 导致 HCT-8/5-FU 细胞和肿瘤组织中 HIF-1α、PI3K、AKT/p-AKT、HKII 和 Glut1 下调，Caspase3 和 Caspase9 上调。在 HIF-1α 沉默的 HCT-8/5-FU 细胞中，协同组 PI3K、AKT、p-AKT 的表达水平明显降低。此外，还观察到 Caspase6 和 Caspase7 的上调表达。JSD 联合 5-FU 也在体内对肿瘤生长表现出明显的抑制作用。JSD 可能通过抑制 PI3K/AKT/HIF-1α 信号通路抑制糖酵解来逆转 5-FU 耐药性，从而抑制糖酵解并诱导细胞凋亡，增强抗肿瘤活性。
