YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels.
Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC, and it often leads to local and distant failure. In this study, we showed that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in human papilloma virus-negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin-resistant cells (CAL27-CisR) as compared with its parent cells (CAL27). Therefore, we hypothesized that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its antiapoptotic function. In a severe combined immunodeficient mouse xenograft model, YM155 significantly enhanced the antitumor and antiangiogenic effects of cisplatin, with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of the chemotherapy in HNSCC.
Department of Otolaryngology–Head and Neck Surgery, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA. Pawan.Kumar@osumc.edu
Bhavna
B
Kumar
Arti
A
Yadav
James C
JC
Lang
Michael J
MJ
Cipolla
Alessandra C
AC
Schmitt
Nicole
N
Arradaza
Theodoros N
TN
Teknos
Pawan
P
Kumar
D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003593:Cytoplasm / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D052162:Human papillomavirus 16; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018709:Statistics, Nonparametric; D000077022:Survivin; D046888:Tissue Array Analysis; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; D002945:Cisplatin; C523798:sepantronium