Cytotoxic Autophagy: A Novel Treatment Paradigm against Breast Cancer Using Oleanolic Acid and Ursolic Acid
Kunj Bihari Gupta1, Jie Gao1,2, Xin Li1,3
1Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
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.
Insights
Oleanolic acid (OA) and Ursolic acid (UA) show anticancer effects at low doses by inducing excessive autophagy in breast cancer cells. Combining OA and UA may be a promising therapeutic strategy for breast cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids with varying reported activities based on dosage.
- In vitro studies show apoptosis at ≥20 µM, but oral administration yields ≤2 µM, limiting clinical efficacy.
- This discrepancy highlights the need to investigate OA and UA efficacy at lower, clinically relevant concentrations.
Purpose of the Study:
- To evaluate the tumor cell-specific cytotoxicity of OA, UA, and their combination at low doses (5-10 µM) in breast cancer (BrCa) cell lines.
- To elucidate the underlying mechanisms of OA and UA-induced cytotoxicity in breast cancer.
- To explore the potential of combining OA and UA with PI3K inhibitors for enhanced breast cancer treatment.
Main Methods:
- Assessed cytotoxicity of OA, UA, and OA + UA on breast cancer cell lines (MCF7, MDA-MB231) and a non-tumorigenic cell line (MCF-12A) at low doses (5-10 µM).
- Investigated mechanisms including apoptosis and autophagy induction, and the role of autophagy-targeting genes (ATGs).
- Analyzed the effect of OA and UA on PI3K/Akt/mTOR signaling pathways and their synergistic effect with a PI3K inhibitor (LY294002).
Main Results:
- Both OA and UA demonstrated significant cytotoxicity against BrCa cells at low doses (5-10 µM), with minimal toxicity to non-tumorigenic cells.
- Cytotoxicity was primarily mediated by excessive autophagy induction, not apoptosis, at 5 µM OA + UA.
- Silencing ATGs abolished OA-, UA-, or OA + UA-induced cell death, confirming the role of autophagy.
- OA and UA treatments inhibited PI3K-mediated phosphorylation of Akt/mTOR, crucial for cancer cell survival.
Conclusions:
- Low-dose OA and UA exhibit potent, tumor-specific cytotoxicity in breast cancer cells, mainly through inducing excessive autophagy.
- Inhibition of PI3K-mediated autophagy appears to be a key mechanism for the anticancer activity of OA and UA.
- Combination therapy with PI3K inhibitors synergistically enhances the anticancer effects of OA and UA, suggesting clinical potential.
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