title: Unique in vitro and in vivo thrombopoietic activities of ingenol 3,20 dibenzoate, a Ca(++)-independent protein kinase C isoform agonist.
abstract: Thrombopoiesis following severe bone marrow injury frequently is delayed, thereby resulting in life-threatening thrombocytopenia for which there are limited treatment options. The reasons for these delays in recovery are not well understood. Protein kinase C (PKC) agonists promote megakaryocyte differentiation in leukemia cell lines and primary cells. However, little is known about the megakaryopoietic effects of PKC agonists on primary CD34+ cells grown in culture or in vivo. Here we present evidence that the novel PKC isoform-selective agonist 3,20 ingenol dibenzoate (IDB) potently stimulates early megakaryopoiesis of human CD34+ cells. In contrast, broad spectrum PKC agonists failed to do so. In vivo, a single intraperitoneal injection of IDB selectively increased platelets in mice without affecting hemoglobin or white counts. Finally, IDB strongly mitigated radiation-induced thrombocytopenia, even when administered 24 hours after irradiation. Our data demonstrate that novel PKC isoform agonists such as IDB may represent a unique therapeutic strategy for accelerating the recovery of platelet counts following severe marrow injury.
authors.affiliation: Department of Pathology, The Ohio State University School of Medicine, Columbus, Ohio, United States of America. frederick.k.racke@questdiagnostics.com
authors.forename: Frederick K
authors.initials: FK
authors.lastname: Racke
authors.forename: Maureen
authors.initials: M
authors.lastname: Baird
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Tianyao
authors.initials: T
authors.lastname: Huo
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Nilendu
authors.initials: N
authors.lastname: Gupta
authors.forename: Michael
authors.initials: M
authors.lastname: Weldon
authors.forename: Heather
authors.initials: H
authors.lastname: Rutledge
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034061:Thrombopoiesis / Q000187:drug effects*
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; D004224:Diterpenes; D007527:Isoenzymes; C011875:ingenol dibenzoate; D011493:Protein Kinase C; D002118:Calcium