期刊
CANCER LETTERS
卷 526, 期 -, 页码 352-362出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.11.014
关键词
Natural diterpenoid; Drug resistance; Reactive oxygen species; Paraptosis; Apoptosis
类别
资金
- Natural Science Foundation of China [81973195, 81973203, 82104020]
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai) [SML2021SP301]
- Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [2017BT01Y093]
- China Postdoctoral Science Foundation [2020M683138]
This study found that the combination therapy of a natural anti-cancer agent Jolkinolide B (JB) and mTOR inhibitors (mTORi) can effectively treat bladder cancer. JB inhibits Akt signaling and cytoprotective autophagy, enhancing the anti-proliferative effects of mTORi. Furthermore, mTORi enhances the pro-apoptotic and pro-paraptotic effects of JB through activating endoplasmic reticulum stress and MAPK pathways.
The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms were related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer.
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