S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Clinical Medical Sciences (임상의과학과) Theses (Ph.D. / Sc.D._임상의과학과)
Clobenpropit Enhances Antitumor Effect of Gemcitabine in Pancreatic Cancer
- 의과대학 임상의과학과
- Issue Date
- 서울대학교 대학원
- Pancreatic neoplasm; Clobenpropit; Histamine; Histamine receptors; Epithelial mesenchymal transition
- 학위논문 (박사)-- 서울대학교 대학원 : 임상의과학과, 2013. 2. 류지곤.
- Introduction: Pancreatic cancer shows dismal prognosis due to early metastasis, frequent recurrence and chemoresistance. However, there is no effective treatment to overcome these problems. Histamine is associated with carcinogenesis through activation of its 4 membrane-specific receptors, thus the agents targeting histamine receptor could be the new therapeutic drug in pancreatic cancer. The aim of this study was to evaluate the anti-tumor effect of clobenpropit, which is the specific H3 antagonist and H4 agonist, with gemcitabine combination in pancreatic cancer cell line.
Methods: Three kinds of human pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and AsPC-1) were used in this study. Expression of H3 and H4 receptor in pancreatic cancer cell was identified with Western blotting. Effects of clobenpropit on cell proliferation, migration, invasion, and apoptosis were evaluated by MTS proliferation assay, wound healing assay, invasion assay and annexin V binding assay. Alteration of epithelial and mesenchymal markers after administration of clobenpropit was analyzed. In vivo study with Panc-1 xenograft mouse model was also performed.
Results: H4 receptors were present as 2 subunits in human pancreatic cancer cells, while there was no expression of H3 receptor. Clobenpropit inhibited migration and increased apoptosis of pancreatic cancer cells in combination with gemcitabine, while did not affect cell invasion property. Clobenpropit upregulated E-cadherin, whereas downregulated vimentin and matrix metalloproteinase 9 in real-time PCR. Also, clobenpropit enhanced apoptosis in combination with gemcitabine by upregulation of E-cadherin and downregulation of Zeb1 in Panc-1 xenograft mouse.
Conclusions: Clobenpropit enhanced antitumor effect of gemcitabine in pancreatic cancer cells through inhibition of EMT process.