Anticancer effects of brusatol in nasopharyngeal carcinoma through suppression of the Akt/mTOR signaling pathway

Abstract

Purpose

Brusatol, a natural quassinoid that is isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, possesses biological activity in various types of human cancers, but its effects in nasopharyngeal carcinoma (NPC) have not been reported. This study aimed to explore the effect and molecular mechanism of brusatol in NPC in vivo and in vitro.

Methods

The antiproliferative effect of brusatol was assessed by MTT and colony formation assays. Apoptosis was determined by flow cytometry. The expression of mitochondrial apoptosis, cell cycle arrest, and Akt/mTOR pathway proteins were determined by western blot analysis. Further in vivo confirmation was performed in a nude mouse model.

Results

Brusatol showed antiproliferative activity against four human NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) in a dose-dependent manner. This antiproliferative effect was accompanied by mitochondrial apoptosis and cell cycle arrest through the modulation of several key molecular targets, such as Bcl-xl, Bcl-2, Bad, Bax, PARP, Caspase-9, Caspase-7, Caspase-3, Cdc25c, Cyclin B1, Cdc2 p34, and Cyclin D1. In addition, we found that brusatol inhibited the activation of Akt, mTOR, 4EBP1, and S6K, suggesting that the Akt/mTOR pathway is a key underlying mechanism by which brusatol inhibits growth and promotes apoptosis. Further in vivo nude mouse models proved that brusatol significantly inhibited the growth of CNE-1 xenografts with no significant toxicity.

Conclusions

These observations indicate that brusatol is a promising antitumor drug candidate or a supplement to current chemotherapeutic therapies to treat NPC.

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Funding

This research was supported by the National College Students’ Innovation Entrepreneurship Training Plan Program of China (No. 201910570006 to S. G.), the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (“Climbing Program” Special Funds) (No. pdjh2019b0403 to S. G.), the Guangzhou Medical University College Students Science Technology Innovation Project (No. 2018A019 to S. G.), the National Natural Science Foundation of China (No. 81672276 to Z. Z.), the Guangzhou Science and Technology Program (No. 201803010038 to Z. Z.), the National Natural Science Foundation of China (No. 21907017 to B. L.), the Guangdong Natural Science Foundation of China (No. 2018A030310186 to B. L.), the Science and Technology Planning Project of Guangdong Province of China (No. A2018377 to B. L.), and the Guangzhou Health and Family Planning Commission of Guangdong Province of China (No. 20181A011068 to B. L.).

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SG designed the study, performed the experiments, analyzed the data and drafted the manuscript. JZ, CW, ZL, RC, DP, HZ and BL participated in a part of the experiments. ZZ conceived the idea and decided on the final manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhenfeng Zhang.

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All procedures performed in involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Cite this article

Guo, S., Zhang, J., Wei, C. et al. Anticancer effects of brusatol in nasopharyngeal carcinoma through suppression of the Akt/mTOR signaling pathway. Cancer Chemother Pharmacol 85, 1097–1108 (2020). https://doi.org/10.1007/s00280-020-04083-3

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Keywords

  • Brusatol
  • Proliferation
  • Apoptosis
  • Nasopharyngeal carcinoma
  • Akt/mTOR pathway