Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
J Ethnopharmacol. 2020 Jun 12;255:112770. doi: 10.1016/j.jep.2020.112770. Epub 2020 Mar 20.
Marsdenia tenacissima extract (MTE) is the water-soluble part of a traditional Chinese medicine Marsdenia tenacissima (Roxb.) Wight & Arn, and is commercially available in China for treating cancers. MTE has been revealed to be effective in improving gefitinib efficacy in treating non-small cell lung cancer (NSCLC). However, the mechanisms remain to be defined.
To determine the effects of MTE on gefitinib metabolism and accumulation in vivo, and to explore the underlying mechanisms.
MTE or vehicle were intraperitoneally administrated to the H1975 xenograft model, followed by intragastric administration of gefitinib 12 h later. Mice plasma, tumors and liver tissues were harvested for further analysis. Hoechst 33342, a specific substrate of ATP Binding Cassette Subfamily G Member 2 (ABCG2), was used to determine the effects of MTE on activities of ABCG2 in tumor cells.
A higher concentration of plasma gefitinib was detected in MTE-treated mice at 24 h after delivery of gefitinib, however, it became insignificant in another 24 h. By contrast, gefitinib levels were continuously higher in MTE-pretreated mice tumor tissues at 12-48 h post gefitinib administration. MTE suppressed plasma levels of gefitinib metabolites (M523595, M608236 and M537194) in the first 24 h after gefitinib delivery, and inhibited activities of liver CYP2D6 and CYP3A4 at early stage (within 6 h) after gefitinib treatment. Strikingly, the activities of ABCG2, the primary drug transporter for gefitinib, were significantly inhibited by MTE in H1975 lung cancer cells. Further, it was identified that tenacissoside H, but not tenacissoside I, may contribute to the ABCG2-suppressive effects of MTE.
MTE pretreatment temporarily elevated plasma concentrations of gefitinib via inhibiting CYP450 enzymes. Most importantly, MTE promoted gefitinib accumulation in tumor tissues in a long-lasting manner via decreasing activities of ABCG2, a drug transporter responsible for gefitinib efflux.
玛斯登苷元提取物（MTE）是一种传统中药玛斯登尼亚坚韧（Roxb.）Wight & Arn 的水溶性部分，在中国可商购用于治疗癌症。已经证明 MTE 可有效提高吉非替尼治疗非小细胞肺癌（NSCLC）的疗效。然而，其机制仍有待确定。
确定 MTE 对吉非替尼在体内代谢和积累的影响，并探讨其潜在机制。
MTE 或载体通过腹腔内给药，然后在 12 小时后通过灌胃给予吉非替尼。采集小鼠血浆、肿瘤和肝脏组织进行进一步分析。Hoechst 33342 是三磷酸腺苷结合盒亚家族 G 成员 2（ABCG2）的特异性底物，用于确定 MTE 对肿瘤细胞 ABCG2 活性的影响。
在给予吉非替尼后 24 小时，给予 MTE 的小鼠血浆中吉非替尼的浓度更高，但在另一个 24 小时后则变得不显著。相比之下，在给予吉非替尼后 12-48 小时，MTE 预处理的小鼠肿瘤组织中的吉非替尼水平持续升高。MTE 在给予吉非替尼后的前 24 小时内抑制了血浆中吉非替尼代谢物（M523595、M608236 和 M537194）的水平，并在吉非替尼治疗早期（6 小时内）抑制了肝 CYP2D6 和 CYP3A4 的活性。令人惊讶的是，MTE 显著抑制了 H1975 肺癌细胞中 ABCG2 的活性，这是吉非替尼的主要药物转运蛋白。此外，鉴定出 Tenacissoside H 而不是 Tenacissoside I 可能有助于 MTE 对 ABCG2 的抑制作用。
MTE 预处理通过抑制 CYP450 酶暂时提高了吉非替尼的血浆浓度。最重要的是，MTE 通过降低负责吉非替尼外排的药物转运蛋白 ABCG2 的活性，以持久的方式促进吉非替尼在肿瘤组织中的积累。
