title: Thiocoraline activates the Notch pathway in carcinoids and reduces tumor progression in vivo.
abstract: Carcinoids are slow-growing neuroendocrine tumors (NETs) that are characterized by hormone overproduction; surgery is currently the only option for treatment. Activation of the Notch pathway has previously been shown to have a role in tumor suppression in NETs. The marine-derived thiodepsipeptide thiocoraline was investigated in vitro in two carcinoid cell lines (BON and H727). Carcinoid cells treated with nanomolar concentrations of thiocoraline resulted in a decrease in cell proliferation and an alteration of malignant phenotype evidenced by decrease of NET markers, achaete-scute complex like-1, chromogranin A and neurospecific enolase. Western blotting analysis demonstrated the activation of Notch1 on the protein level in BON cells. Additionally, thiocoraline activated downstream Notch targets HES1, HES5 and HEY2. Thiocoraline effectively suppressed carcinoid cell growth by promoting cell cycle arrest in BON and H727 cells. An in vivo study demonstrated that thiocoraline, formulated with polymeric micelles, slowed carcinoid tumor progression. Thus the therapeutic potential of thiocoraline, which induced activation of the Notch pathway, in carcinoid tumors was demonstrated.
authors.affiliation: Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Wyche
authors.affiliation: Department of Surgery Endocrine Research Laboratories, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dammalapati
authors.affiliation: Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Surgery Endocrine Research Laboratories, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Harrison
authors.affiliation: Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Kwon
authors.affiliation: Department of Surgery Endocrine Research Laboratories, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Bugni
authors.affiliation: Department of Surgery Endocrine Research Laboratories, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jaskula-Sztul
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002276:Carcinoid Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047630:Depsipeptides; D051880:Receptors, Notch; C109005:thiocoraline