title: Crucial role of heme oxygenase-1 in the sensitivity of acute myeloid leukemia cell line Kasumi-1 to ursolic acid.
abstract: Ursolic acid (UA), which has been used extensively as an antileukemic agent in traditional Chinese medicine, is safely edible if originating from food. We found that the apoptotic rate of acute myeloid leukemia (AML) subtype M2 (AML-M2) cell line Kasumi-1 treated by UA was higher than those of other leukemia cell lines, but was not as high as that treated by arabinofuranosyl cytidine (Ara-C), suggesting that UA is an important chemotherapeutic agent to treat AML-M2. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation, and drug resistance. HO-1 in Kasumi-1 cells was upregulated by being treated with low-dose rather than high-dose UA. Inhibition of HO-1 by zinc protoporphyrin (ZnPP) IX sensitized Kasumi-1 cells to UA, and the apoptotic rate was close to that induced by Ara-C (P<0.01). The sensitizing effect of ZnPP was associated with caspase activation, bcl-2 downregulation, and PARP activation. After silencing HO-1 by siRNA transfection with lentivirus, the cells' proliferation induced by UA was increased as it was by Ara-C. Furthermore, combining ZnPP with UA prolonged the survival of mice bearing the AML subtype M2 tumor with smaller volume of tumor and size of spleen. The results showed that the Kasumi-1 cell line was the most sensitive to UA, but the apoptotic effect was inferior to that treated by Ara-C because of HO-1 upregulation. AML-M2 can feasibly be treated by target-inhibiting HO-1 that enhances the antileukemia effects of UA in vitro and in vivo.
authors.affiliation: aDepartment of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical College Departments of bPharmacy cHematology dGuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guiyang Medical College eKey Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.forename: Yaming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuying
authors.initials: X
authors.lastname: Hu
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Shengshu
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D011524:Protoporphyrins / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D000097245:Ursolic Acid
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D003561:Cytarabine; D051547:Heme Oxygenase-1; D011524:Protoporphyrins; D014315:Triterpenes; D000097245:Ursolic Acid; C017803:zinc protoporphyrin