title: Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma.
abstract: Malignant mesothelioma is a devastating disease with a poor prognosis for which there is a clear need for more successful therapeutic approaches. Triptolide, a diterpenoid triepoxide, is a highly effective agent against several cancer types in animal models. Owing to triptolide's poor solubility in water, a water-soluble analog, minnelide, was synthesized. Minnelide is a prodrug of triptolide and is activated by exposure to phosphatases that are found in all body tissues, including blood. Mesothelioma cells were treated in vitro with minnelide or its parent compound, triptolide. Minnelide and triptolide were both found to significantly reduce mesothelioma cell viability and induce apoptosis. The level of Hsp70, a protein that promotes cancer cell survival, was measured in mesothelioma cells before and after treatment with triptolide. Hsp70 levels were decreased in a dose-dependent manner. In addition, triptolide sensitized cells to gemcitabine and pemetrexed as measured by cell viability. Mice bearing mesothelioma flank tumors were treated with daily injections (28 d) of minnelide or saline solution and xenograft tumor growth recorded. Mice displayed significantly reduced tumor burden. These findings support the clinical evaluation of minnelide therapy for mesothelioma.
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Jacobson
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Esther Z
authors.initials: EZ
authors.lastname: Chen
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Shaogeng
authors.initials: S
authors.lastname: Tang
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Holly Sedgwick
authors.initials: HS
authors.lastname: Belgum
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: McCauley
authors.affiliation: Departments of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Evenson
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Etchison
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Jay-Dixon
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Raza
authors.affiliation: Departments of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
authors.affiliation: Departments of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: D'Cunha
authors.affiliation: Departments of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kratzke
keywords: Hsp70; Triptolide; mesothelioma; minnelide