title: Inhibition of CDK9 induces apoptosis and potentiates the effect of cisplatin in hypopharyngeal carcinoma cells.
abstract: Myeloid cell leukemia-1 (Mcl-1) plays an important role in survival, chemo- and radioresistance of head and neck squamous cell carcinoma (HNSCC). Cyclin-dependent kinase 9/cyclin T (CDK9) promotes excessive production of multiple pro-survival proteins including Mcl-1, leading to impaired apoptosis of cancer cells. As such, CDK9 is an emerging therapeutic target in cancer therapy. We herein report the first study of targeting CDK9 as a treatment strategy for hypopharyngeal squamous cell carcinoma (HSCC), an aggressive malignancy associated with one of the worst prognoses within HNSCC. We showed that mRNA levels of Mcl-1 were significantly higher in HSCC tumor tissues than in the adjacent non-tumor mucosae. In addition, the levels of Mcl-1 mRNA correlated with the tumor size and clinical stage of HSCC patients. CDKI-73, a potent CDK9 inhibitor, was capable of downregulating the expression of Mcl-1 in the HSCC cells by suppression of the CDK9 mediated phosphorylation of RNA polymerase II. CDKI-73 effectively induced apoptosis as a single agent and synergized anti-tumor activity of cisplatin in HSCC cells. Taken together, our study presents compelling evidence for developing CDK9 inhibitors, such as CDKI-73, as new therapeutic strategy for HSCC.
authors.affiliation: Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China.
authors.forename: Shengda
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Shandong, PR China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China.
authors.forename: Shangren
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Lei
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute of Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA5000, Australia.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Key Laboratory of Otolaryngology, Chinese Ministry of Health, Shandong, PR China. Electronic address: xinliang_pan@163.com.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Shandong, PR China. Electronic address: junpeng88@sina.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007013:Hypopharynx / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D042863:Cyclin-Dependent Kinase 9; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C000599930:3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide; D000096926:Benzenesulfonamides; C579095:MCL1 protein, human
keywords: Apoptosis; CDK9 inhibition; Chemosensitization; Cisplatin; Hypopharyngeal squamous cell carcinoma; Mcl-1