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

// Li Xie 1, * , Xingguo Song 1, * , Wei Guo 2 , Xingwu Wang 1 , Ling Wei 1 , Yang Li 1 , Liyan Lv 1 , Weijun Wang 3 , Thomas C. Chen 3 , Xianrang Song 1 1 Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China 2 Ultrasound Diagnosis Department, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China 3 Department 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 G 2 /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.