Oncotarget

Research Papers:

Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation

Li Xie, Xingguo Song, Wei Guo, Xingwu Wang, Ling Wei, Yang Li, Liyan Lv, Weijun Wang, Thomas C. Chen and Xianrang Song _

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Oncotarget. 2016; 7:1651-1662. https://doi.org/10.18632/oncotarget.6410

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Abstract

Li Xie1,*, Xingguo Song1,*, Wei Guo2, Xingwu Wang1, Ling Wei1, Yang Li1, Liyan Lv1, Weijun Wang3, Thomas C. Chen3, Xianrang Song1

1Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China

2Ultrasound Diagnosis Department, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China

3Department of Neurological Surgery and Pathology, University of Southern California, Los Angeles, CA, United States

*These authors contributed equally to this work

Correspondence to:

Xianrang Song, e-mail: basiclab@163.com

Keywords: nasopharyngeal carcinoma (NPC), reactive oxygen species (ROS), temozolomide (TMZ), perillyl alcohol (POH)

Received: July 16, 2015     Accepted: November 20, 2015     Published: November 27, 2015

ABSTRACT

Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy without efficient chemotherapeutic agents for it. In our current study, we demonstrated the cytotoxicity effects of a newly patented compound temozolomide–perillyl alcohol (TMZ-POH) on NPC in vitro and in vivo, and the possible mechanisms involved. Human NPC cell lines CNE1, CNE2, HNE2, and SUME-α were treated with control (DMSO), TMZ, POH, TMZ plus POH, and TMZ-POH. Our data indicated that TMZ-POH could inhibit NPC cell proliferation, cause G2/M arrest and DNA damage. TMZ-POH triggered apoptosis in NPC cells via significant activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). Importantly, TMZ-POH-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (ΔΨm) and release of mitochondrial Cytochrome c, (ii) the increase in ROS generation, and (iii) the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinases (JNK) signaling pathway. The generation of ROS in response to TMZ-POH seems to play a crucial role in the cell death process since the blockage of ROS production using the antioxidant N-acetyl-L-cysteine or catalase reversed the TMZ-POH-induced JNK activation, DNA damage, and cancer cell apoptosis. These results provide the rationale for further research and preclinical investigation of the antitumor effect of TMZ-POH against human NPC.


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