title: Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation.
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.
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Song
authors.affiliation: Ultrasound Diagnosis Department, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Xingwu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Neurological Surgery and Pathology, University of Southern California, Los Angeles, CA, United States of America.
authors.forename: Weijun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurological Surgery and Pathology, University of Southern California, Los Angeles, CA, United States of America.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, China.
authors.forename: Xianrang
authors.initials: X
authors.lastname: Song
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D039821:Monoterpenes / Q000008:administration & dosage / Q000494:pharmacology; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D039821:Monoterpenes; D017382:Reactive Oxygen Species; C032208:perillyl alcohol; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D000077204:Temozolomide
keywords: nasopharyngeal carcinoma (NPC); perillyl alcohol (POH); reactive oxygen species (ROS); temozolomide (TMZ)