Hirsutanol A, a novel sesquiterpene compound from fungus Chondrostereum sp., induces apoptosis and inhibits tumor growth through mitochondrial-independent ROS production: hirsutanol A inhibits tumor growth through ROS production.

Abstract

BACKGROUND:

Hirsutanol A is a novel sesquiterpene compound purified from fungus Chondrostereum sp. in Sarcophyton tortuosum. Our previous studies had demonstrated that hirsutanol A exhibited potent cytotoxic effect on many kinds of cancer cell lines. In the current study, the antitumor activity of hirsutanol A and its molecular mechanisms were investigated.

METHODS:

Hirsutanol A induced growth inhibition and apoptotic cell death of human colon cancer SW620 cells and human breast cancer MDA-MB-231cells were determined using MTT assay and flow cytometry assay, respectively. The effect of hirsutanol A on intrinsic ROS level and change in mitochondrial membrane potential (△ψm) of different cell lines were also measured by flow cytometry assay. The function of JNK was compromised by JNK siRNA or JNK inhibitor SP600125. The expression of cytochrome c, p-JNK, p-c-Jun after treatment with hirsutanol A were detected by Western blot analysis. Finally, the in vivo anti-tumor effect of hirsutanol A was examined in human cancer cell SW620 xenograft model.

RESULTS:

The results showed that hirsutanol A significantly induced apoptosis, mitochondrial-independent increase of Reactive Oxygen Species (ROS) level, change of mitochondrial membrane potential, release of cytochrome c in human cancer cells. Preventing increase of ROS level using the potent antioxidant N-acetyl-L-cysteine (NAC) markedly decreased hirsutanol A-induced apoptosis. In addition, JNK signaling pathway was activated by hirsutanol A through elevating ROS level. Blockade of JNK signaling pathway by JNK specific inhibitor SP600125 enhanced apoptosis and hirsutanol A-induced ROS accumulation. Also, hirsutanol A exhibited antitumor activity in human cancer cell SW620 xenograft model.

CONCLUSION:

These data suggested that hirsutanol A inhibited tumor growth through triggering ROS production and apoptosis.

• Authors: Fen Yang, Wen-Dan Chen, Rong Deng, Hui Zhang, Jun Tang, Ke-Wei Wu, Dan-Dan Li, Gong-Kan Feng, Wen-Jian Lan, Hou-Jin Li, Xiao-Feng Zhu
• Journal: Journal of translational medicine (J Transl Med) Vol. 11 Pg. 32 (Feb 08 2013) ISSN: 1479-5876 [Electronic] England
• PMID: 23394457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Sesquiterpenes
• Tetrazolium Salts
• Thiazoles
• hirsutanol A
• Cytochromes c
• thiazolyl blue

Topics

• Agaricales (metabolism)
• Animals
• Apoptosis
• Cell Death
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Cytosol (metabolism)
• Flow Cytometry
• Humans
• Membrane Potentials
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism)
• Neoplasm Transplantation
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes (pharmacology)
• Signal Transduction
• Tetrazolium Salts (pharmacology)
• Thiazoles (pharmacology)