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

  • Clin Cancer Res. 2019 Sep 15;25(18):5650-5662. doi: 10.1158/1078-0432.CCR-19-0096.
Antje Lindemann   #  1 ,  Ameeta A Patel   #  1 ,  Natalie L Silver  2 ,  Lin Tang  3 ,  Zhiyi Liu  1 ,  Li Wang  4 ,  Noriaki Tanaka  5 ,  Xiayu Rao  6 ,  Hideaki Takahashi  1 ,  Nakachi K Maduka  1 ,  Mei Zhao  1 ,  Tseng-Cheng Chen  7 ,  WeiWei Liu  8 ,  Meng Gao  1 ,  Jing Wang  6 ,  Steven J Frank  4 ,  Walter N Hittelman  9 ,  Gordon B Mills  10 ,  Jeffrey N Myers   #  11 ,  Abdullah A Osman   #  11
Affiliations
  • 1. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2. Department of Otolaryngology, Division of Head and Neck Oncologic Surgery, University of Florida College of Medicine, Gainesville, Florida.
  • 3. Department of Cellular and Molecular Medicine, The University of Arizona Health Sciences, College of Medicine, Tucson, Arizona.
  • 4. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5. Department of Dentistry and Oral Surgery, Osaka Police Hospital, Osaka, Japan.
  • 6. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 7. Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
  • 8. Department of Oral Surgery, School of Stomatology, Jilin University, Changchun, Jilin, China.
  • 9. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer, Houston, Texas.
  • 10. Oregon Health & Science University, Knight Cancer Institute, Portland, Oregon.
  • 11. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. [email protected] [email protected].
  • # Contributed equally.
PMID: 31308060 DOI: 10.1158/1078-0432.CCR-19-0096
Abstract

Purpose: TP53 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 TP53-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 TP53 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 TP53 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 TP53 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 TP53 mutations.

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