title: Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathways.
abstract: Leukemia has been the third type of cancer killing many people across the world. Bakkenolide A (Bak), extracted from Petasites tricholobus, has been suggested to against cancer and display protective effects on inflammatory cytokines formation. And increasing evidences suggest that histone deacetylase 3 (HDAC3) plays vital roles in cancer formation and persistence via cell death, apoptosis and inflammation. But the function of Bakkenolide A in regulating leukemia is not understood yet, particularly via HDAC3. Here, we found that HDAC3 is up-regulated in clinical samples of leukemia compared with adjacent normal tissues. Then the expression of HDAC3 was knocked down via RNA interference in K562 cells. And inhibition of HDAC3 expression is able to improve leukemia invasion, migration and proliferation. Further, we also found HDAC3 bound to IκBα, affecting subsequent inflammation response. Moreover, Bakkenolide A was found to inhibit inflammation, induce apoptosis and cell death in leukemia cells via PI3K-regulated signaling pathway, down-regulating IKKs expression and suppressing in proinflammatory cytokines of IL-1β, IL-18 and TNF-α. Up-regulation of Caspase3/7 was observed in cells of HDAC3-knockdown and Bakkenolide A treatment, inducing leukemia cell apoptosis. Also, the expression of Akt and GSK were activated by HDAC3-knockdown and Bakkenolide A-treatment. Thus, these results indicated that Bakkenolide A-mediated HDAC3 sensitization in leukemia cells seem to be associated with activation of effector IKKs, Akt/GSK, and caspases through induction of the PI3K pathway, leading to inflammation, cell death, and apoptosis.
authors: Department of Pediatrics, Huai'an Hospital Affiliated of Xuzhou Medical University and Huai'an Second People's Hospital, No. 62 Huaihai Road South, Huai'an 223002, China.
authors: Lei
authors: L
authors: Zhang
authors: Department of Pediatrics, Huai'an First People's Hospital, Affiliated of Nanjing Medical University, No. 6 Beijing Road West, Huai'an, Jiangsu 223300, China.
authors: Ze
authors: Z
authors: Hong
authors: Department of Pediatrics, Huai'an First People's Hospital, Affiliated of Nanjing Medical University, No. 6 Beijing Road West, Huai'an, Jiangsu 223300, China.
authors: Rong-Rong
authors: RR
authors: Zhang
authors: Department of Pediatrics, Huai'an First People's Hospital, Affiliated of Nanjing Medical University, No. 6 Beijing Road West, Huai'an, Jiangsu 223300, China.
authors: Xing-Zhen
authors: XZ
authors: Sun
authors: Department of Pediatrics, Huai'an First People's Hospital, Affiliated of Nanjing Medical University, No. 6 Beijing Road West, Huai'an, Jiangsu 223300, China.
authors: Yu-Fang
authors: YF
authors: Yuan
authors: Department of Pediatrics, Huai'an First People's Hospital, Affiliated of Nanjing Medical University, No. 6 Beijing Road West, Huai'an, Jiangsu 223300, China.
authors: Jian
authors: J
authors: Hu
authors: Department of Pediatrics, Huai'an First People's Hospital, Affiliated of Nanjing Medical University, No. 6 Beijing Road West, Huai'an, Jiangsu 223300, China. Electronic address: wangxiang480380@126.com.
authors: Xiang
authors: X
authors: Wang
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012717:Sesquiterpenes; D000099186:Histone Deacetylase 3; C016257:bakkenolide A
keywords: Bakkenolide A; HDAC3; Leukemia; PI3K