1. Enhancement of Histone Deacetylase Inhibitor Sensitivity in Combination with Cyclin-Dependent Kinase Inhibition for the Treatment of Oral Squamous Cell Carcinoma
- Author
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Xin Wang, Yongtao Li, Chenhua Yu, Zhi Huang, Shengyong Yang, Zhongxiang Qin, Tianqi Wang, Linchuan Wang, Wei Zhou, Rong Xiang, Yan Fan, and Borui Zhao
- Subjects
0301 basic medicine ,Male ,STAT3 Transcription Factor ,Epithelial-Mesenchymal Transition ,Physiology ,medicine.drug_class ,Transplantation, Heterologous ,Down-Regulation ,Mice, Nude ,Apoptosis ,lcsh:Physiology ,lcsh:Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cyclin-dependent kinase ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:QD415-436 ,Protein Kinase Inhibitors ,Cell Proliferation ,Mice, Inbred BALB C ,lcsh:QP1-981 ,biology ,Cell growth ,Chemistry ,Kinase ,Histone deacetylase inhibitor ,Janus Kinase 1 ,Cell cycle ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Pyrimidines ,Terminal deoxynucleotidyl transferase ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Carcinoma, Squamous Cell ,Benzimidazoles ,Mouth Neoplasms ,Histone deacetylase ,Signal Transduction - Abstract
Background/aims Previous research has indicated that the currently available histone deacetylase inhibitors (HDACis) are not effective as monotherapies against oral squamous cell carcinoma (OSCC). However, HDACis act synergistically with other therapeutic agents to exert significant antitumor activities. Thus, a strategy to develop chemotherapeutic agents by combining several active groups based on histone deacetylase (HDAC) into a single molecule as a conjugate that modulates multiple cellular pathways may be useful for the treatment of OSCC. Methods The novel inhibitor Roxyl-ZR was prepared by organic synthesis and its anticancer effects on OSCC were investigated by cell metabolism (n=5), colony formation (n=3), cell cycle (n=3), cell apoptosis (n=3), wound healing (n=3), transwell migration (n=3), and 5-bromo-2'-deoxyuridine staining (n=3) assays in vitro and in in vivo xenograft mice models (4 mice/group for subcutaneous xenograft and 3 mice/group for orthotopic xenograft ). The abundance of Ki67, Bcl-2, and p-STAT3 was detected by immunohistochemistry staining (n=4). Apoptotic cells in the tumor tissues of mice were detected by terminal deoxynucleotidyl transferase dUTP nickend labeling assay (n=3). The abundance of related proteins levels were evaluated by western blot (n=3). E-cadherin expression was detected by an immunofluorescence assay (n=3). Results Compared with the approved HDACi, conjugated Roxyl-ZR exhibited significantly higher antitumor effects in OSCC cells. Roxyl-ZR suppressed OSCC cell proliferation by inducing the reduction of S phase and inducing caspase-dependent apoptosis by down-regulating Bcl-2 expression. Moreover, Roxyl-ZR attenuated the epithelial-mesenchymal transition, which is closely associated with migration and invasion. In addition, Roxyl-ZR inhibited OSCC xenograft mice models and showed low toxicity. The mechanism underlying the Roxyl-ZR-enhanced sensitivity to HDACi may be attributed to the inhibition of key regulators of JAK1-STAT3 signaling pathway. Conclusion HDAC-cyclin-dependent kinase conjugates represent a novel approach to the development of OSCC treatment. Our findings may open a new avenue for the development of novel inhibitors for the treatment of OSCC.
- Published
- 2017