Efficacy of poly (ADP-ribose) polymerase inhibitor olaparib against head and neck cancer cells: Predictions of drug sensitivity based on PAR-p53-NF-κB interactions.
Poly (ADP-ribose) polymerase (PARP) is a key molecule in the DNA damage response (DDR), which is a major target of both chemotherapies and radiotherapies. PARP inhibitors therefore comprise a promising class of anticancer therapeutics. In this study, we evaluated the efficacy of the PARP inhibitor olaparib, and also sought to identify the mechanism and predictive marker associated with olaparib sensitivity in head and neck cancer (HNC) cells. A total of 15 HNC cell lines, including AMC HNC cells, were tested. AMC-HN3 and HN4 exhibited stronger responses to olaparib. Among cisplatin-resistant cell lines, only AMC HN9-cisR cells were significantly suppressed by olaparib. We found that basal poly (ADP-ribose) (PAR) levels, but not PARP-1 levels, correlated with olaparib sensitivity. AMC-HN3 and HN4 cells exhibited higher basal levels of NF-κB that decreased significantly after olaparib treatment. In contrast, apoptotic proteins were intrinsically expressed in AMC-HN9-cisR cells. As interference with p53 expression led to NF-κB reactivation, we concluded that elevated basal PAR and NF-κB levels are predictive of olaparib responsiveness in HNC cells; in addition, olaparib inhibits HNC cells via PAR-p53-NF-κB interactions.
a Department of Otorhinolaryngology , Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine , Changwon , Republic of Korea.
Minsu
M
Kwon
b Department of Otolaryngology , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea.
Hyejin
H
Jang
b Department of Otolaryngology , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea.
Eun Hye
EH
Kim
b Department of Otolaryngology , Asan Medical Center, University of Ulsan College of Medicine , Seoul , Republic of Korea.
Jong-Lyel
JL
Roh
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016328:NF-kappa B; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; C531550:olaparib
NF-κB; PARP inhibitor; head and neck cancer; olaparib; p53; poly (ADP-ribose)
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