Background: Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment. Materials and Methods: The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231. Results: The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation. Discussion: Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells. Conclusion: These results suggest it would be worthwhile testing combined OA and UA in clinical settings.
背景：齐墩果酸（OA）与熊果酸（UA）是具有生物活性的三萜类化合物。已有报道显示，其体外活性随测试剂量不同而变化。使用≥20 µM剂量的研究表明其在癌细胞中具有诱导凋亡的活性。然而，口服UA和OA后达到的循环血药浓度报道值≤2 µM，这限制了它们用于治疗或联合治疗的应用。 材料与方法：本研究报告展示了OA、UA以及OA+UA在低剂量（5 µM至10 µM）下对乳腺癌细胞系MCF7和MDA-MB231的肿瘤细胞特异性细胞毒性作用。 结果：数据显示，OA和UA在低剂量下均能杀伤乳腺癌细胞，但对非致瘤性细胞系MCF-12A的毒性显著较低。此外，≤10 µM的OA+UA对乳腺癌细胞具有致死作用。机制研究表明，在OA和UA各5 µM的剂量下，细胞凋亡显著缺失，其细胞毒性源于诱导了过度的自噬。通过沉默自噬靶向基因（ATGs）可阻止OA、UA或OA+UA诱导的细胞死亡，从而证实其细胞毒性与药物诱导的细胞毒性自噬相关。此外，UA或OA+UA处理乳腺癌细胞会抑制PI3激酶介导的Akt/mTOR磷酸化，这是调控癌细胞存活、代谢和增殖的关键通路。 讨论：PI3K抑制剂（LY294002）与OA、UA或OA+UA联用能协同抑制乳腺癌细胞存活。因此，通过抑制PI3K介导的自噬而引发的细胞毒性自噬主导作用，可能是PTT诱导乳腺癌细胞抗癌活性的主要机制。 结论：这些结果表明，在临床环境中测试OA与UA的联合应用具有重要价值。
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