naphthoquinones and Carcinoma--Neuroendocrine

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a rare and heterogenous tumor entity. Importantly, the highly proliferative subgroup of neuroendocrine carcinoma (GEP-NEC) is characterized by high resistance to conventional chemotherapy. Consequently, there is an urgent need to identify novel therapeutic targets, especially for GEP-NEC. Thus, we focused on Inhibitor of apoptosis protein (IAP) family members survivin and XIAP that orchestrate inhibition of apoptosis, induce resistance against chemotherapeutics and facilitate tumor metastasis. Copy number gains (CNGs) could be detected by microarray comparative genomic hybridization for survivin and XIAP in 60 % and 26.7 % of all GEP-NENs, respectively. Immunohistochemical staining of tissue specimens from 77 consecutive patients with GEP-NEN demonstrated increased survivin protein expression levels in tissue specimens of highly proliferative GEP-NEC or GEP-NEN located in the stomach and colon. In contrast, XIAP overexpression was associated with advanced tumor stages. Knockdown of survivin and XIAP markedly reduced cell proliferation and tumor growth. In vitro, YM155 induced apoptotic cell death accompanied by a reduction in cell proliferation and inhibited GEP-NEC xenograft growth. Taken together, our data provide evidence for a biological relevance of these IAPs in GEP-NEN and support a potential role of survivin as therapeutic target especially in the subgroup of aggressive GEP-NEC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Proliferation; Comparative Genomic Hybridization; DNA Copy Number Variations; Dose-Response Relationship, Drug; Female; Gene Dosage; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Intestinal Neoplasms; Male; Masoprocol; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Naphthoquinones; Oligonucleotide Array Sequence Analysis; Pancreatic Neoplasms; Retrospective Studies; RNA Interference; Signal Transduction; Stomach Neoplasms; Survivin; Time Factors; Transfection; Tumor Burden; X-Linked Inhibitor of Apoptosis Protein; Xenograft Model Antitumor Assays