title: Inhibition of chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN) by capsaicin in LSL-KrasG12D/Pdx1-Cre mice.
abstract: Capsaicin is a major biologically active ingredient of chili peppers. Extensive studies indicate that capsaicin is a cancer-suppressing agent via blocking the activities of several signal transduction pathways including nuclear factor-kappaB, activator protein-1 and signal transducer and activator of transcription 3. However, there is little study on the effect of capsaicin on pancreatic carcinogenesis. In the present study, the effect of capsaicin on pancreatitis and pancreatic intraepithelial neoplasia (PanIN) was determined in a mutant Kras-driven and caerulein-induced pancreatitis-associated carcinogenesis in LSL-Kras(G12D)/Pdx1-Cre mice. Forty-five LSL-Kras(G12D)/Pdx1-Cre mice and 10 wild-type mice were subjected to one dose of caerulein (250 μg/kg body wt, intraperitoneally) at age 4 weeks to induce and synchronize the development of chronic pancreatitis and PanIN lesions. One week after caerulein induction, animals were randomly distributed into three groups and fed with either AIN-76A diet, AIN-76A diet containing 10 p.p.m. capsaicin or 20 p.p.m. capsaicin for a total of 8 weeks. The results showed that capsaicin significantly reduced the severity of chronic pancreatitis, as determined by evaluating the loss of acini, inflammatory cell infiltration and stromal fibrosis. PanIN formation was frequently observed in the LSL-Kras(G12D)/Pdx1-Cre mice. The progression of PanIN-1 to high-grade PanIN-2 and -3 were significantly inhibited by capsaicin. Further immunochemical studies revealed that treatment with 10 and 20 p.p.m. capsaicin significantly reduced proliferating cell nuclear antigen-labeled cell proliferation and suppressed phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun as well blocked Hedgehog/GLI pathway activation. These results indicate that capsaicin could be a promising agent for the chemoprevention of pancreatic carcinogenesis, possibly via inhibiting pancreatitis and mutant Kras-led ERK activation.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Ward 6-118, Chicago, IL 60611, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Bai
authors.forename: Haonan
authors.initials: H
authors.lastname: Li
authors.forename: Wanying
authors.initials: W
authors.lastname: Zhang
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Matkowskyj
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002211:Capsaicin / Q000627:therapeutic use*; D002212:Capsicum / Q000737:chemistry*; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic; D002108:Ceruletide / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology*; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018689:Sensory System Agents / Q000627:therapeutic use; D015534:Trans-Activators / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D018689:Sensory System Agents; D015534:Trans-Activators; D018808:Transcription Factor AP-1; C084010:pancreatic and duodenal homeobox 1 protein; D002108:Ceruletide; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D002211:Capsaicin