Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer.
Anticancer drug development strategies critically involve the identification of novel molecular targets which are crucial for tumorigenesis and metastasis. In this context, the molecular chaperone heat-shock protein 90 (Hsp90) has gained interest as a promising anticancer drug target, due to its importance in maintaining the stability, integrity, conformation and function of key oncogenic proteins. These Hsp90 "client proteins" have been demonstrated to play fundamental roles in the processes of signal transduction, cell proliferation and survival, cell cycle progression and apoptosis, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. The cancer selectivity and antitumoral effects of Hsp90 inhibitors are mediated by simultaneous and combined actions, in terms of directly affecting multiple cancer targets and pathways. Several Hsp90 inhibitors, including the geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG), have displayed convincing antineoplastic efficacy and cancer selectivity in a variety of preclinical models, including gastrointestinal carcinomas. Importantly, some Hsp90 inhibitors have now progressed to phase I/II clinical testing. Against this background, the following review focuses on the current preclinical experience and value of targeting Hsp90 for the therapy of gastrointestinal carcinomas.
Moser
Christian
C
Department of Surgery, University of Regensburg Medical Center, 93042 Regensburg, Germany.
Lang
Sven A
SA
Stoeltzing
Oliver
O
D000818:Animals; D016227:Benzoquinones / Q000627:therapeutic use*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin