Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway

Zhang, Dong-Mei; Liu, Jun-Shan; Deng, Li-Juan; Chen, Min-Feng; Yiu, Anita; Cao, Hui-Hui; Tian, Hai-Yan; Fung, Kwok-Pui; Kurihara, Hiroshi; Pan, Jing-Xuan; Ye, Wen-Cai
June 2013
Carcinogenesis;Jun2013, Vol. 34 Issue 6, p1331
Academic Journal
Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Currently, only sorafenib, a multitargeted tyrosine kinase inhibitor, slightly improves survival in HCC patients. In searching for natural anti-HCC components from toad venom, which is frequently used in the treatment of liver cancer in traditional Chinese medicine, we discovered that arenobufagin, a bufadienolide from toad venom, had potent antineoplastic activity against HCC HepG2 cells as well as corresponding multidrug-resistant HepG2/ADM cells. We found that arenobufagin induced mitochondria-mediated apoptosis in HCC cells, with decreasing mitochondrial potential, as well as increasing Bax/Bcl-2 expression ratio, Bax translocation from cytosol to mitochondria. Arenobufagin also induced autophagy in HepG2/ADM cells. Autophagy-specific inhibitors (3-methyladenine, chloroquine and bafilomycin A1) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced arenobufagin-induced apoptosis, indicating that arenobufagin-mediated autophagy may protect HepG2/ADM cells from undergoing apoptotic cell death. In addition, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by arenobufagin. Interestingly, inhibition of mTOR by rapamycin or siRNA duplexes augmented arenobufagin-induced apoptosis and autophagy. Finally, arenobufagin inhibited the growth of HepG2/ADM xenograft tumors, which were associated with poly (ADP-ribose) polymerase cleavage, light chain 3-II activation and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of arenobufagin on HCC cells both in vitro and in vivo. We elucidated the underlying antineoplastic mechanisms of arenobufagin that involve cross talk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway. This study may provide a rationale for future clinical application using arenobufagin as a chemotherapeutic agent for HCC.


Related Articles

  • Galectin-1-Induced Autophagy Facilitates Cisplatin Resistance of Hepatocellular Carcinoma. Su, Yu-Chi; Davuluri, Goutham Venkata Naga; Chen, Cheng-Hao; Shiau, Dong-Che; Chen, Chien-Chin; Chen, Chia-Ling; Lin, Yee-Shin; Chang, Chih-Peng // PLoS ONE;2/9/2016, Vol. 11 Issue 2, p1 

    Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor...

  • Natural small-molecule enhancers of autophagy induce autophagic cell death in apoptosis-defective cells. Betty Yuen Kwan Law; Wai Kit Chan; Su Wei Xu; Jing Rong Wang; Li Ping Bai; Liang Liu; Vincent Kam Wai Wong // Scientific Reports;7/4/2014, p1 

    Resistance of cancer cells to chemotherapy is a significant problem in oncology, and the development of sensitising agents or small-molecules with new mechanisms of action to kill these cells is needed. Autophagy is a cellular process responsible for the turnover of misfolded proteins or damaged...

  • Induction of autophagy and senescence by knockdown of ROC1 E3 ubiquitin ligase to suppress the growth of liver cancer cells. Yang, D; Li, L; Liu, H; Wu, L; Luo, Z; Li, H; Zheng, S; Gao, H; Chu, Y; Sun, Y; Liu, J; Jia, L // Cell Death & Differentiation;Feb2013, Vol. 20 Issue 2, p235 

    Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell...

  • Heat-Modified Citrus Pectin Induces Apoptosis-Like Cell Death and Autophagy in HepG2 and A549 Cancer Cells. Leclere, Lionel; Fransolet, Maude; Cote, Francois; Cambier, Pierre; Arnould, Thierry; Van Cutsem, Pierre; Michiels, Carine // PLoS ONE;Mar2015, Vol. 10 Issue 3, p1 

    Cancer is still one of the leading causes of death worldwide, and finding new treatments remains a major challenge. Previous studies showed that modified forms of pectin, a complex polysaccharide present in the primary plant cell wall, possess anticancer properties. Nevertheless, the mechanism...

  • Ulinastatin Reduces the Resistance of Liver Cancer Cells to Epirubicin by Inhibiting Autophagy. Song, Bin; Bian, Qi; Shao, Cheng Hao; Li, Gang; Liu, An An; Jing, Wei; Liu, Rui; Zhang, Yi-Jie; Zhou, Ying-Qi; Hu, Xian-Gui; Jin, Gang // PLoS ONE;Mar2015, Vol. 10 Issue 3, p1 

    During chemotherapy, drug resistance caused by autophagy remains a major challenge to successful treatment of cancer patients. The purpose of this study is to show that ulinastatin (UTI), a trypsin inhibitor, could reduce the resistance of liver cancer cells to chemotherapeutic agent epirubicin...

  • Keyword Index for Volume 109.  // British Journal of Cancer;12/10/2013, Vol. 109 Issue 12, p3145 

    A subject index of several keywords for the 2013 issue of "British Journal of Cancer" is presented including apoptosis, autophagy and cancer chemoprevention.

  • Suppression of RAF/MEK or PI3K synergizes cytotoxicity of receptor tyrosine kinase inhibitors in glioma tumor-initiating cells. Takashi Shingu; Holmes, Lindsay; Henry, Verlene; Qianghu Wang; Latha, Khatri; Gururaj, Anupama E.; Gibson, Laura A.; Doucette, Tiffany; Lang, Frederick F.; Ganesh Rao; Liang Yuan; Sulman, Erik P.; Farrell, Nicholas P.; Priebe, Waldemar; Hess, Kenneth R.; Wang, Yaoqi A.; Jian Hu; Bögler, Oliver; Shingu, Takashi; Wang, Qianghu // Journal of Translational Medicine;2/9/2016, Vol. 14, p1 

    Background: The majority of glioblastomas have aberrant receptor tyrosine kinase (RTK)/RAS/phosphoinositide 3 kinase (PI3K) signaling pathways and malignant glioma cells are thought to be addicted to these signaling pathways for their survival and proliferation. However, recent...

  • Scutellarininduces human hepatocellular carcinoma cells apoptosis through increasing autophagy. Peng Li; Nan Geng; Runtian Liu; Congjing An; Yun Bai; Jianxing Zheng // International Journal of Clinical & Experimental Medicine;2016, Vol. 9 Issue 7, p13890 

    Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. It is urgent to develop novel effective agents in the field of liver cancer therapy. Although Scutellarin (Scu) has shown great potential as a new approach for cancer treatment, the inhibitory role of Scu...

  • c-Cbl targets active Src for autophagy. Cecconi, Francesco // Nature Cell Biology;Jan2012, Vol. 14 Issue 1, p48 

    Autophagy can promote both cancer cell survival and death, and the mechanisms by which it mediates these disparate processes are under intense investigation. Autophagosomes are now shown to entrap and promote degradation of the active tyrosine kinase Src, enabling tumour cell survival. The E3...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics