Claudia Stutz, Ana Paula Gregório Alves Fontão, Gustavo Werneck de Souza E Silva, Leonardo Noboru Seito, Renata Trentin Perdomo, André Luiz Franco Sampaio
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引用次数: 0
摘要
慢性髓性白血病(CML)是一种骨髓增生性疾病,其特点是存在癌基因BCR-ABL。甲磺酸伊马替尼(IMA)是治疗慢性骨髓性白血病的一线药物,但也有一些耐药性的报道。天然产品是具有生物效应的生物活性化合物的丰富来源,为改变细胞对伊马替尼等药物的敏感性提供了可能。在此,我们采用 Chou-Talalay 法评估了白桦脂酸和熊果酸对糖蛋白 P (P-gp) 活性的干扰以及与 IMA 联用时可能产生的协同效应。熊果酸对 K562 和 Lucena 1 的 IC50 分别为 14.0μM 和 19.6μM,而白桦脂酸对这些细胞株的 IC50 分别为 8.6μM 和 12.5μM。对萜类化合物和甲磺酸伊马替尼的组合进行评估后发现,熊果酸或白桦脂酸与 IMA 具有协同作用,组合指数(CI
Betulinic Acid Acts in Synergism with Imatinib Mesylate, Triggering Apoptosis in MDR Leukemia Cells.
Chronic myeloid leukemia (CML) is a myeloproliferative disease, characterized by the presence of the oncogene BCR-ABL. Imatinib mesylate (IMA) is the first-line treatment for CML, and some treatment resistance has been reported. Natural products are rich sources of bioactive compounds with biological effects, opening a possibility to alter cell susceptibility to drugs such as imatinib. Herein, we evaluated the interference of betulinic acid and ursolic acid in glycoprotein P (P-gp) activity and the possible synergistic effect when associated with IMA by the Chou-Talalay method. Ursolic acid presented an IC50 of 14.0 µM and 19.6 µM for K562 and Lucena 1, respectively, whilst betulinic acid presented an IC50 of 8.6 µM and 12.5 µM for these cell lines. Evaluation of the combination of terpenoids and imatinib mesylate revealed that ursolic acid or betulinic acid acts in synergism with IMA, as indicated by the combination indexes (CI<1). Analysis of annexin V labeling demonstrated that a combination of IMA with betulinic acid enhances the inhibition on cell proliferation via the apoptosis pathway, with caspases 3/7 activation after 24 hours of treatment and inhibition of the STAT5/survivin pathway, decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant leukemia cell line is a promising strategy for CML treatment.
期刊介绍:
Planta Medica is one of the leading international journals in the field of natural products – including marine organisms, fungi as well as micro-organisms – and medicinal plants. Planta Medica accepts original research papers, reviews, minireviews and perspectives from researchers worldwide. The journal publishes 18 issues per year.
The following areas of medicinal plants and natural product research are covered:
-Biological and Pharmacological Activities
-Natural Product Chemistry & Analytical Studies
-Pharmacokinetic Investigations
-Formulation and Delivery Systems of Natural Products.
The journal explicitly encourages the submission of chemically characterized extracts.