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The decoy binds to STAT3, abrogating its ability to bind to DNA response elements and induce transcription of target genes, resulting in decreased proliferation and increased apoptosis

The decoy binds to STAT3, abrogating its ability to bind to DNA response elements and induce transcription of target genes, resulting in decreased proliferation and increased apoptosis. at several levels, including the upstream receptor, the intracellular transcription element, 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 element decoy, we found enhanced antitumor effects in vitro and in vivo. The combination of the STAT3 decoy and gossypol, a small molecule focusing on Bcl-XL, 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 Maxacalcitol 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 restorative strategy for SCCHN. Approximately 500, 000 instances of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed yearly worldwide, and they account for approximately 3% of all cancers in the United States. SCCHN, CD300E an epithelial malignancy that affects the top aerodigestive tract mucosa, has been linked to chronic tobacco and alcohol use. Conventional restorative strategies including surgery, chemotherapy, and radiation are effective in only 50% of instances, underscoring the need for new approaches to treat this malignancy. Recent studies have focused on combining inhibitors that target several molecules in one signaling pathway known to contribute to malignancy progression to enhance antitumor effectiveness. Epidermal growth element receptor (EGFR) overexpression has been detected in a variety of human being malignancies, including SCCHN in which expression levels in the tumor are correlated with decreased patient survival (Rubin Grandis et al., 1998; Ang et al., 2002). Transmission transducer and activator of transcription (STAT)-3 is definitely triggered downstream of EGFR in SCCHN, and studies possess demonstrated a role for STAT3 as an oncogene (Bromberg et al., 1998; Turkson et al., 1998). Constitutive activation of STAT3 has been detected in many cancers, including multiple myeloma, leukemia, lymphoma, prostate, breast, pancreas, lung, ovary, as well as SCCHN. A key downstream target of STAT3 is the gene encoding Bcl-XL, an antiapoptotic member of the Bcl-2 protein family. Overexpression of Bcl-XL Maxacalcitol has been reported in a majority of SCCHN, and it correlates with resistance to chemotherapy (Trask et al., 2002). We previously shown the feasibility of using a double-stranded deoxynucleotide transcription element decoy to target triggered STAT3, and we showed the STAT3 decoy exhibited antitumor effects in SCCHN preclinical models, both only and in combination with cytotoxic chemotherapy (Ahonen et al., 2003; Leong et al., 2003). The decoy binds to STAT3, abrogating its ability to bind to DNA response elements and induce transcription of target genes, resulting in decreased proliferation and improved apoptosis. To day, no STAT3 focusing on strategy has been approved for the treatment of cancer. In this study, we investigated the antitumor effectiveness of combining the STAT3 decoy with the tyrosine kinase inhibitor erlotinib (OSI-774; Tarceva), the bad enantiomer of gossypol Maxacalcitol (AT-101), or both, in preclinical models of SCCHN. Erlotinib has shown significant antitumor effects against SCCHN, and it is currently approved by the United States Food and Drug Administration (2004) for treatment of locally advanced or metastatic nonCsmall-cell lung malignancy after failure of at least one prior chemotherapy routine and for use in combination with gemcitabine for the first-line treatment of individuals with locally advanced, unresectable or metastatic pancreatic malignancy (Pomerantz and Grandis, 2004). However, focusing on of EGFR only offers only demonstrated promise clinically when combined with standard cytotoxic methods, Maxacalcitol including chemotherapy or radiation, in SCCHN (Burtness et al., 2005; Bonner et al., 2006). To day, no Bcl-XL Maxacalcitol inhibitors have been investigated in individuals with SCCHN. Studies have shown the bad.