COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms.

Autor:	Lindemann A; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Patel AA; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Silver NL; Department of Otolaryngology, Division of Head and Neck Oncologic Surgery, University of Florida College of Medicine, Gainesville, Florida., Tang L; Department of Cellular and Molecular Medicine, The University of Arizona Health Sciences, College of Medicine, Tucson, Arizona., Liu Z; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wang L; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Tanaka N; Department of Dentistry and Oral Surgery, Osaka Police Hospital, Osaka, Japan., Rao X; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Takahashi H; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Maduka NK; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zhao M; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chen TC; Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan., Liu W; Department of Oral Surgery, School of Stomatology, Jilin University, Changchun, Jilin, China., Gao M; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wang J; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Frank SJ; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hittelman WN; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer, Houston, Texas., Mills GB; Oregon Health & Science University, Knight Cancer Institute, Portland, Oregon., Myers JN; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. jmyers@mdanderson.org aaosman@mdanderson.org., Osman AA; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. jmyers@mdanderson.org aaosman@mdanderson.org.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Sep 15; Vol. 25 (18), pp. 5650-5662. Date of Electronic Publication: 2019 Jul 15.
DOI:	10.1158/1078-0432.CCR-19-0096
Abstrakt:	Purpose: TP 53 mutations are highly prevalent in head and neck squamous cell carcinoma (HNSCC) and associated with increased resistance to conventional treatment primarily consisting of chemotherapy and radiation. Restoration of wild-type p53 function in TP 53-mutant cancer cells represents an attractive therapeutic approach and has been explored in recent years. In this study, the efficacy of a putative p53 reactivator called COTI-2 was evaluated in HNSCC cell lines with different TP 53 status. Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine in vitro and in vivo sensitivity of HNSCC cell lines with either wild-type, null, or mutant TP 53 to COTI-2 alone, and in combination with cisplatin and/or radiation. Western blotting, cell cycle, live-cell imaging, RNA sequencing, reverse-phase protein array, chromatin immunoprecipitation, and apoptosis analyses were performed to dissect molecular mechanisms. Results: COTI-2 decreased clonogenic survival of HNSCC cells and potentiated response to cisplatin and/or radiation in vitro and in vivo irrespective of TP 53 status. Mechanistically, COTI-2 normalized wild-type p53 target gene expression and restored DNA-binding properties to the p53-mutant protein in HNSCC. In addition, COTI-2 induced DNA damage and replication stress responses leading to apoptosis and/or senescence. Furthermore, COTI-2 lead to activation of AMPK and inhibition of the mTOR pathways in vitro in HNSCC cells. Conclusions: COTI-2 inhibits tumor growth in vitro and in vivo in HNSCC likely through p53-dependent and p53-independent mechanisms. Combination of COTI-2 with cisplatin or radiation may be highly relevant in treating patients with HNSCC harboring TP 53 mutations. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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