State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.
Cancer center, Medical Research Institute, Southwest University, Chongqing, 400716, China.
J Exp Clin Cancer Res. 2020 Oct 30;39(1):230. doi: 10.1186/s13046-020-01743-3.
Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment.
The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).
In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer.
The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.
盐酸石蒜碱（LH）是从石蒜鳞茎中提取的一种生物碱，具有抗病毒、抗疟疾和抗肿瘤作用。目前，LH 治疗胃癌的作用机制尚不清楚。BCL2 家族的抗凋亡蛋白 MCL1 与肿瘤耐药密切相关。因此，MCL1 被认为是癌症治疗的潜在靶点。
通过 MTT、BrdU、western blot 等体外实验和免疫组化等体内实验评估 LH 对胃癌的作用。
本研究表明，LH 通过下调胃癌中的 MCL1 发挥抗肿瘤作用。此外，我们揭示 LH 通过上调泛素 E3 连接酶 FBXW7 降低 MCL1 蛋白稳定性，使细胞周期停滞在 S 期并引发胃癌细胞凋亡。同时，我们还证明 LH 可诱导 BCL2 耐药细胞系的凋亡。此外，PDX（患者来源的肿瘤异种移植）模型实验证明，LH 联合 HA14-1（BCL2 抑制剂）对胃癌有更显著的治疗效果。
我们的数据表明盐酸石蒜碱是一种有前途的胃癌抗肿瘤化合物。
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