Arsenic trioxide inhibits tumor cell growth in malignant rhabdoid tumors in vitro and in vivo by targeting overexpressed Gli1

• Published in: International journal of cancer 2014-08, Vol.135 (4), p.989-995
• Main Authors: Kerl, Kornelius, Moreno, Natalia, Holsten, Till, Ahlfeld, Julia, Mertins, Julius, Hotfilder, Marc, Kool, Marcel, Bartelheim, Kerstin, Schleicher, Sabine, Handgretinger, Rupert, Schüller, Ulrich, Meisterernst, Michael, Frühwald, Michael C.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Arsenic; arsenic trioxide; Arsenicals - pharmacology; Biological and medical sciences; Cancer; Cell Cycle; Cell growth; Cell Proliferation; Chinese medicine; Computational Biology; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gli1; Hedgehog Proteins - metabolism; Humans; Kruppel-Like Transcription Factors - metabolism; Leukemia; Medical research; Medical sciences; Mice; Mice, SCID; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Transplantation; Oxides - pharmacology; Prognosis; Rhabdoid Tumor - drug therapy; rhabdoid tumors; Signal Transduction; Sonic hedgehog; Transcription Factors - metabolism; Tumors; Zinc Finger Protein GLI1
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28719

Rhabdoid tumors are highly aggressive tumors occurring in infants and very young children. Despite multimodal and intensive therapy prognosis remains poor. Molecular analyses have uncovered several deregulated pathways, among them the CDK4/6‐Rb‐, the WNT‐ and the Sonic hedgehog (SHH) pathways. The SHH pathway is activated in rhabdoid tumors by GLI1 overexpression. Here, we demonstrate that arsenic trioxide (ATO) inhibits tumor cell growth of malignant rhabdoid tumors in vitro and in a mouse xenograft model by suppressing Gli1. Our data uncover ATO as a promising therapeutic approach to improve prognosis for rhabdoid tumor patients. What's new? Rhabdoid tumors are highly aggressive tumors of infants and very young children. Despite multimodal and intensive therapeutic approaches, prognosis remains poor. Molecular analyses have linked rhabdoid tumors with dysregulations in the Sonic hedgehog pathway. Here, the authors demonstrate that low doses of arsenic trioxide, a compound originally used in traditional Chinese medicine and homeopathy, inhibit cell growth of malignant rhabdoid tumors in vitro and in a xenograft model by downregulating Gli1, the immediate downstream activator of the Sonic hedgehog pathway. As arsenic trioxide is approved for the treatment of acute promyelocytic leukemia and has efficacy in other tumors, it may become an interesting new treatment option in children with rhabdoid tumors.