(-)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo

Keith G. Wolter; Steven J. Wang; Bradley S. Henson; Shaomeng Wang; Kent A. Griffith; Bhavna Kumar; Jianyong Chen; Thomas E. Carey; Carol R. Bradford; Nisha J. D'Silva

doi:10.1593/neo.05691

(-)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo

Keith G. Wolter, Steven J. Wang, Bradley S. Henson, Shaomeng Wang, Kent A. Griffith, Bhavna Kumar, Jianyong Chen, Thomas E. Carey, Carol R. Bradford, Nisha J. D'Silva

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111 Scopus citations

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.

Original language	English (US)
Pages (from-to)	163-172
Number of pages	10
Journal	Neoplasia
Volume	8
Issue number	3
DOIs	https://doi.org/10.1593/neo.05691
State	Published - Mar 2006
Externally published	Yes

Keywords

(-)-Gossypol
Bcl-x
Chemoresistance
Head and neck cancer
Oral cancer

ASJC Scopus subject areas

Cancer Research

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10.1593/neo.05691

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@article{7a7a5310d14440b6879fdcaa76e0c58b,

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-xL. (-)-Gossypol, the negative enantiomer of a cottonseed polyphenol, binds to Bcl-xL 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-xL 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.",

keywords = "(-)-Gossypol, Bcl-x, Chemoresistance, Head and neck cancer, Oral cancer",

author = "Wolter, {Keith G.} and Wang, {Steven J.} and Henson, {Bradley S.} and Shaomeng Wang and Griffith, {Kent A.} and Bhavna Kumar and Jianyong Chen and Carey, {Thomas E.} and Bradford, {Carol R.} and D'Silva, {Nisha J.}",

note = "Funding Information: Address all correspondence to: Nisha J. D{\textquoteright}Silva, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Room 5217, Ann Arbor, MI 48109-1078. E-mail: [email protected] 1This research was supported by National Institute of Dental and Craniofacial Research (NIDCR) grants DE00452-01 (N.J.D.), DE014620-01A1 (B.S.H.), and R01 DE13346 (T.E.C.); National Cancer Institute (NCI) grant R01 CA83087 (C.R.B.); Department of Defense idea grant BC000914; the Susan G. Komen Breast Cancer Foundation; the CapCure Foundation (S.W.); the University of Michigan{\textquoteright}s NCI Cancer Center support grant 5 P30 CA46592; Head and Neck Cancer SPORE grant P50 CA97248; and NIDCD Research Center Core grant P30 DC05188 (multiple authors). S.J.W. and K.G.W. were funded by National Institutes of Health training grant T32 DC05356. S.W. has financial interests in Ascenta Pharmaceuticals, which is pursuing the production of (−)-gossypol and other compounds for clinical use. 2Keith G. Wolter and Steven J. Wang contributed equally to this manuscript.",

year = "2006",

month = mar,

doi = "10.1593/neo.05691",

language = "English (US)",

volume = "8",

pages = "163--172",

journal = "Neoplasia",

issn = "1522-8002",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - (-)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo

AU - Wolter, Keith G.

AU - Wang, Steven J.

AU - Henson, Bradley S.

AU - Wang, Shaomeng

AU - Griffith, Kent A.

AU - Kumar, Bhavna

AU - Chen, Jianyong

AU - Carey, Thomas E.

AU - Bradford, Carol R.

AU - D'Silva, Nisha J.

N1 - Funding Information: Address all correspondence to: Nisha J. D’Silva, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Room 5217, Ann Arbor, MI 48109-1078. E-mail: [email protected] 1This research was supported by National Institute of Dental and Craniofacial Research (NIDCR) grants DE00452-01 (N.J.D.), DE014620-01A1 (B.S.H.), and R01 DE13346 (T.E.C.); National Cancer Institute (NCI) grant R01 CA83087 (C.R.B.); Department of Defense idea grant BC000914; the Susan G. Komen Breast Cancer Foundation; the CapCure Foundation (S.W.); the University of Michigan’s NCI Cancer Center support grant 5 P30 CA46592; Head and Neck Cancer SPORE grant P50 CA97248; and NIDCD Research Center Core grant P30 DC05188 (multiple authors). S.J.W. and K.G.W. were funded by National Institutes of Health training grant T32 DC05356. S.W. has financial interests in Ascenta Pharmaceuticals, which is pursuing the production of (−)-gossypol and other compounds for clinical use. 2Keith G. Wolter and Steven J. Wang contributed equally to this manuscript.

PY - 2006/3

Y1 - 2006/3

N2 - 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-xL. (-)-Gossypol, the negative enantiomer of a cottonseed polyphenol, binds to Bcl-xL 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-xL 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.

AB - 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-xL. (-)-Gossypol, the negative enantiomer of a cottonseed polyphenol, binds to Bcl-xL 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-xL 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.

KW - (-)-Gossypol

KW - Bcl-x

KW - Chemoresistance

KW - Head and neck cancer

KW - Oral cancer

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U2 - 10.1593/neo.05691

DO - 10.1593/neo.05691

M3 - Article

C2 - 16611409

AN - SCOPUS:33646375977

SN - 1522-8002

VL - 8

SP - 163

EP - 172

JO - Neoplasia

JF - Neoplasia

IS - 3

ER -

(-)-Gossypol inhibits growth and promotes apoptosis of human head and neck squamous cell carcinoma in vivo

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