Discovery of Aloperine as a Potential Antineoplastic Agent for Cholangiocarcinoma Harboring Mutant IDH1

被引：1

作者：

Wu, Xingkang ^{[1
]}

Li, Yang ^{[1
]}

Han, Chenchen ^{[1
]}

Li, Shifei ^{[2
]}

Qin, Xuemei ^{[1
]}

机构：

[1] Shanxi Univ, Modern Res Ctr Tradit Chinese Med, Key Lab Chem Biol & Mol Engn, Minist Educ, 92 Wucheng Rd, Taiyuan 030006, Peoples R China

[2] Shanxi Univ, Inst Mol Sci, Key Lab Chem Biol & Mol Engn, Educ Minist, 92 Wucheng Rd, Taiyuan 030006, Peoples R China

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2024年 / 25卷 / 17期

关键词：

quinolizidine alkaloids; aloperine; intrahepatic cholangiocarcinoma; D-2-hydroxyglutarate; IDH mutation; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; CELLS; APOPTOSIS; PROLIFERATION; METABOLISM; MUTATION; MATRINE;

D O I：

10.3390/ijms25179226

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH.

引用

页数：15

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