"N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Kashirskoye shosse 24, 115478, Moscow, Russia.
Institute of Technical Chemistry of Ural Branch of the Russian Academy of Sciences, Acad. Korolev St. 3, 614013, Perm, Russia.
Chem Biol Interact. 2021 Oct 1;348:109645. doi: 10.1016/j.cbi.2021.109645. Epub 2021 Sep 10.
Semi-synthetic A-cycle modified triterpenic derivatives with A-cycle condensed with a heterocyclic fragment (compound 1) and fragmented A-ring (compound 2) were tested for cytotoxicity against several tumor cell cultures and doxorubicin (Dox)-resistant cell lines. The equal cytotoxicity of the tested compounds to the parental tumor cell lines (HBL-100, K562) and their resistant subclones (HBL-100/Dox, K562/i-S9) was revealed. The overexpression of ABCB1 (MDR1) gene and P-glycoprotein (P-gp) was confirmed for both resistant subclones of tumor cells. Compounds 1 and 2 were shown to inhibit the ABC-transporter gene expression (MDR1, MRP, MVP, and BCRP) and the transport of well-known P-gp substrate Rhodamine 123 from resistant cells. The docking of triterpenoids 1 and 2 into the drug binding site of P-gp revealed a similarity between the conformation of the tested triterpenoids and that of classical inhibitor verapamil, thus assuming these compounds to be more likely the inhibitors than the substrates of P-gp. Any tested triterpenic derivatives, when combined at non-toxic concentrations with doxorubicin, improved cytotoxic effect of the therapeutic drug against resistant subclones of tumor cells.
半合成 A 环修饰的三萜衍生物，其中 A 环与杂环片段（化合物 1）和断裂的 A 环（化合物 2）缩合，对几种肿瘤细胞培养物和多柔比星（Dox）耐药细胞系进行了细胞毒性测试。测试化合物对亲本肿瘤细胞系（HBL-100、K562）及其耐药亚克隆（HBL-100/Dox、K562/i-S9）具有相同的细胞毒性。证实了两种耐药肿瘤细胞亚克隆均过度表达 ABCB1（MDR1）基因和 P-糖蛋白（P-gp）。化合物 1 和 2 被证明可抑制 ABC 转运蛋白基因表达（MDR1、MRP、MVP 和 BCRP），并可从耐药细胞中抑制已知的 P-gp 底物 Rhodamine 123 的转运。三萜 1 和 2 与 P-gp 的药物结合位点对接表明，测试的三萜的构象与经典抑制剂维拉帕米的构象相似，因此假定这些化合物更可能是 P-gp 的抑制剂而不是底物。任何测试的三萜衍生物在与多柔比星联合使用时，在非毒性浓度下均可提高治疗药物对耐药肿瘤细胞亚克隆的细胞毒性作用。
