Survivin and YM155: how faithful is the liaison?
Survivin belongs to the family of apoptosis inhibitors (IAPs), which antagonizes the induction of cell death. Dysregulated expression of IAPs is frequently observed in cancers, and the high levels of survivin in tumors compared to normal adult tissues make it an attractive target for pharmacological interventions. The small imidazolium-based compound YM155 has recently been reported to block the expression of survivin via inhibition of the survivin promoter. Recent data, however, question that this is the sole and main effect of this drug, which is already being tested in ongoing clinical studies. Here, we critically review the current data on YM155 and other new experimental agents supposed to antagonize survivin. We summarize how cells from various tumor entities and with differential expression of the tumor suppressor p53 respond to this agent in vitro and as murine xenografts. Additionally, we recapitulate clinical trials conducted with YM155. Our article further considers the potency of YM155 in combination with other anti-cancer agents and epigenetic modulators. We also assess state-of-the-art data on the sometimes very promiscuous molecular mechanisms affected by YM155 in cancer cells.
Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
Anke
A
Rauch
Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
Dorle
D
Hennig
Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
Claudia
C
Schäfer
II Department of Internal Medicine, Technical University of Munich, Munich, Germany.
Matthias
M
Wirth
Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
Christian
C
Marx
Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
Thorsten
T
Heinzel
II Department of Internal Medicine, Technical University of Munich, Munich, Germany.
Günter
G
Schneider
Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131 Mainz, Germany. Electronic address: okraemer@uni-mainz.de.
Oliver H
OH
Krämer
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009285:Naphthoquinones / Q000008:administration & dosage*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium
Cancer; Chemotherapy; Molecular target; Specificity; Survivin; YM155