Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model.

Abstract

The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety of tumor types. In this study, we used BK5.erbB2 transgenic mice as an animal model to examine the therapeutic effect of rapamycin as a potential treatment for gallbladder cancer. Homozygous BK5.erbB2 mice overexpressing the wild-type rat erbB2 gene in basal epithelial cells of the gallbladder have an approximately 70% incidence of gallbladder adenocarcinoma by 2 to 3 months of age. Groups of mice ( approximately 2-3 months of age) were treated with rapamycin by i.p. injection (once daily for 14 days) and then sacrificed 24 h after the last treatment. Rapamycin significantly reduced the incidence and severity of gallbladder carcinoma in BK5.erbB2 mice in a dose-dependent manner. Tumors responsive to treatment exhibited a higher number of apoptotic cells. Furthermore, rapamycin treatment led to decreased levels of phosphorylated p70 S6 kinase (Thr(389)) in gallbladder tissue as assessed by both Western blot and immunofluorescence analyses. Finally, immunofluorescence staining revealed elevated phosphorylated Akt (Ser(473)) and phosphorylated mammalian target of rapamycin (mTOR; Ser(2448)) in human gallbladder cancer compared with normal gallbladder tissue. Based on our results using a novel genetically engineered mouse model and the fact that the Akt/mTOR pathway is activated in human gallbladder cancer, rapamycin and related drugs may be effective therapeutic agents for the treatment of human gallbladder cancer.

• Authors: Qi Wu, Kaoru Kiguchi, Toru Kawamoto, Tetsuo Ajiki, Jeanine Traag, Steve Carbajal, Lynnsie Ruffino, Howard Thames, Ignacio Wistuba, Melanie Thomas, Karen M Vasquez, John DiGiovanni
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 8 Pg. 3794-800 (Apr 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17440093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• mTOR protein, rat
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adenocarcinoma (drug therapy, metabolism)
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Female
• Gallbladder Neoplasms (drug therapy, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred ICR
• Mice, Transgenic
• Phosphorylation (drug effects)
• Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases