title: Inactivation of FoxM1 transcription factor contributes to curcumin-induced inhibition of survival, angiogenesis, and chemosensitivity in acute myeloid leukemia cells.
abstract: Aberrant expression of forkhead box protein M1 (FoxM1) contributes to carcinogenesis in human cancers, including acute myeloid leukemia (AML), suggesting that the discovery of specific agents targeting FoxM1 would be extremely valuable for the treatment of AML. Curcumin, a naturally occurring phenolic compound, is suggested to possess anti-leukemic activity; however, the underlying mechanism has not been well elucidated. In this study, we found that curcumin inhibited cell survival accompanied by induction of G2/M cell cycle arrest and apoptosis in HL60, Kasumi, NB4, and KG1 cells. This was associated with concomitant attenuation of FoxM1 and its downstream genes, such as cyclin B1, cyclin-dependent kinase (CDK) 2, S-phase kinase-associated protein 2, Cdc25B, survivin, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, and vascular endothelial growth factor (VEGF), as well as the reduction of the angiogenic effect of AML cells. We also found that specific downregulation of FoxM1 by siRNA prior to curcumin treatment resulted in enhanced cell survival inhibition and induction of apoptosis. Accordingly, FoxM1 siRNA increased the susceptibility of AML cells to doxorubicin-induced apoptosis. More importantly, curcumin suppressed FoxM1 expression, selectively inhibited cell survival as well as the combination of curcumin and doxorubicin exhibited a more inhibitory effect in primary CD34(+) AML cells, while showing limited lethality in normal CD34(+) hematopoietic progenitors. These results identify a novel role for FoxM1 in mediating the biological effects of curcumin in human AML cells. Our data provide the first evidence that curcumin together with chemotherapy or FoxM1 targeting agents may be effective strategies for the treatment of AML.
  
  
  CONCLUSIONS
  Curcumin inhibited AML cell survival and angiogenesis and induced chemosensitivity. Aberrant expression of FoxM1 induces AML cell survival and chemoresistance. Inactivation of FoxM1 contributes to curcumin-induced anti-leukemic effects. Curcumin together with FoxM1 targeting agents may be effective for AML therapy.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, West Wenhua Rd. 107, Jinan, 250012, Shandong, People's Republic of China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Dong
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Dao-Xin
authors.initials: DX
authors.lastname: Ma
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Ji
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D004317:Doxorubicin; D003474:Curcumin