title: (-)-gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo.
abstract: Resistance to chemotherapy is a common problem encountered in the treatment of head and neck squamous cell carcinoma (HNSCC). Chemoresistant HNSCC tumors frequently overexpress antiapoptotic proteins, such as Bcl-x(L). (-)-gossypol, the negative enantiomer of a cottonseed polyphenol, binds to Bcl-x(L) and was recently been shown to inhibit HNSCC proliferation in vitro. In this study, we assessed the in vivo efficacy of (-)-gossypol in an orthotopic xenograft model of HNSCC, using two human HNSCC cell lines with high Bcl-x(L) expression levels. Both produced tumors in a murine floor-of-mouth model that mimics human HNSCC, exhibiting growth and invasion into adjacent tissues. Mice were randomized into three groups: vehicle control and two daily intraperitoneal (-)-gossypol treatment groups (5 and 15 mg/kg). Tumors were measured twice weekly. In the control group, tumors grew progressively, whereas in (-)-gossypol treatment groups, tumor growth was significantly suppressed. The mitotic rate in tumors from (-)-gossypol-treated animals was significantly lower than that in controls, and an increase in the percentage of apoptotic cells was observed in treated tumors versus controls. Residual tumors remained growth-suppressed for 2 weeks after cessation of (-)-gossypol treatment. Our results demonstrate that (-)-gossypol can inhibit tumor growth in an orthotopic model of aggressive HNSCC.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA.
authors.forename: Keith G
authors.initials: KG
authors.lastname: Wolter
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Wang
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Henson
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Kent A
authors.initials: KA
authors.lastname: Griffith
authors.forename: Bhavna
authors.initials: B
authors.lastname: Kumar
authors.forename: Jianyong
authors.initials: J
authors.lastname: Chen
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Carey
authors.forename: Carol R
authors.initials: CR
authors.lastname: Bradford
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: D'Silva
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000637:transplantation; D002478:Cells, Cultured / Q000187:drug effects; D006072:Gossypol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007274:Injections, Intraperitoneal; D015603:Keratinocytes / Q000187:drug effects; D007822:Laryngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008940:Mitotic Index; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D009363:Neoplasm Proteins; D051020:bcl-X Protein; D006072:Gossypol