Research Papers:

Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species

Jiasheng Chen, Binshen Chen, Zhihui Zou, Wei Li, Yiming Zhang, Jinlin Xie and Chunxiao Liu _

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Oncotarget. 2017; 8:107701-107715. https://doi.org/10.18632/oncotarget.22592

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Jiasheng Chen1,*, Binshen Chen1,*, Zhihui Zou1,*, Wei Li2, Yiming Zhang1, Jinlin Xie1 and Chunxiao Liu1

1Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China

2Department of Urological Surgery, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 18000, China

*These authors contributed equally to this work

Correspondence to:

Chunxiao Liu, email: [email protected]

Keywords: costunolide; apoptosis; prostate cancer; reactive oxygen species; MAPK

Received: June 08, 2017     Accepted: November 04, 2017     Published: November 21, 2017


The management of castration-resistant prostate cancer (CRPC) is challenging, attributable to a lack of efficacious therapies. Chemotherapy is one of the most important treatments for CRPC. Doxorubicin has been extensively used in many different tumors and is often combined with other drugs to enhance effects and reduce toxicity. Costunolide is a natural sesquiterpene lactone with anti-cancer properties. In this study, we first demonstrated that the combination of costunolide and doxorubicin induced apoptosis significantly more than either drug alone in prostate cancer cell lines. Costunolide combined with doxorubicin induced mitochondria-mediated apoptosis through a loss of mitochondrial membrane potential and modulation of Bcl-2 family proteins. We found that this drug combination significantly increased the production of reactive oxygen species (ROS), as well as phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, which play upstream roles in mitochondria-mediated apoptosis. Further studies showed that N-acetyl cysteine blocked JNK and p38 phosphorylation, suggesting that ROS were upstream activators of JNK and p38. However, a JNK inhibitor, but not a p38 inhibitor, blocked the increase in ROS observed in cells treated with a combination of costunolide and doxorubicin, suggesting that ROS and JNK could activate each other. In vivo, inhibition of tumor growth and induction of apoptosis were greater in mice treated with the costunolide and doxorubicin combination than in mice treated with either drug alone, without an increase in toxicity. Therefore, we suggested that costunolide in combination with doxorubicin was a new potential chemotherapeutic strategy for treating prostate cancer.

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