Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-XL enhances antitumor effects in squamous cell carcinoma of the head and neck

被引:55
作者
Boehm, Amanda L. [1 ]
Sen, Malabika [2 ]
Seethala, Raja [1 ]
Gooding, William E. [5 ]
Freilino, Maria [2 ]
Wong, Silvia Man Yan [2 ]
Wang, Shaomeng [6 ]
Johnson, Daniel E. [3 ,4 ]
Grandis, Jennifer Rubin [2 ,3 ]
机构
[1] Univ Pittsburgh, Inst Canc, Dept Pathol, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Inst Canc, Dept Otolaryngol, Pittsburgh, PA 15213 USA
[3] Univ Pittsburgh, Inst Canc, Dept Pharmacol, Pittsburgh, PA 15213 USA
[4] Univ Pittsburgh, Inst Canc, Dept Med, Pittsburgh, PA 15213 USA
[5] Univ Pittsburgh, Inst Canc, Dept Biostat, Pittsburgh, PA 15213 USA
[6] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA
关键词
D O I
10.1124/mol.107.044636
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Squamous cell carcinoma of the head and neck (SCCHN) is a leading cause of cancer deaths worldwide. Epidermal growth factor receptor (EGFR), an upstream mediator of signal transducer and activator of transcription (STAT)-3 is overexpressed in a variety of cancers, including SCCHN. Therapies such as monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have demonstrated limited antitumor efficacy, which may be explained, in part, by persistent STAT3 activation despite EGFR inhibition. STAT3 activation induces expression of target genes in SCCHN, including Bcl-X-L, a mediator of antiapoptotic activity. Bcl-X-L is commonly overexpressed in SCCHN where it correlates with chemoresistance, making it a potential therapeutic target. Targeting the EGFR-STAT3-Bcl-X-L pathway at several levels, including the upstream receptor, the intracellular transcription factor, and the downstream target gene, has not been investigated previously. Using erlotinib, an EGFR-specific reversible tyrosine kinase inhibitor in combination with a STAT3 transcription factor decoy, we found enhanced antitumor effects in vitro and in vivo. The combination of the STAT3 decoy and gossypol, a small molecule targeting Bcl-X-L, also yielded enhanced inhibition of cell proliferation. The triple combination of erlotinib, STAT3 decoy, and gossypol further enhanced cell growth inhibition and apoptosis in vitro, and it down-regulated signaling molecules further downstream of the EGFR-STAT3 signaling pathway, such as cyclin D1. These results suggest that combined targeting of several components of an oncogenic signaling pathway may be an effective therapeutic strategy for SCCHN.
引用
收藏
页码:1632 / 1642
页数:11
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