Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy.

Abstract

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.

• Authors: Jun Sang, Lu Gan, Ming-Feng Zou, Zi-Jun Lin, Run-Zhu Fan, Jia-Luo Huang, Wei Li, Gui-Hua Tang, Sheng Yin
• Journal: Cancer letters (Cancer Lett) Vol. 526 Pg. 352-362 (02 01 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34798195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Diterpenes
• Drugs, Chinese Herbal
• MTOR Inhibitors
• jolkinolide B
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Autophagy (drug effects)
• Cell Line, Tumor
• Diterpenes (pharmacology, therapeutic use)
• Drugs, Chinese Herbal (pharmacology, therapeutic use)
• Humans
• MTOR Inhibitors (pharmacology, therapeutic use)
• Male
• Mice
• Proto-Oncogene Proteins c-akt (drug effects)
• Signal Transduction
• Transfection
• Urinary Bladder Neoplasms (drug therapy)