title: Cell cycle arrest, apoptosis and autophagy induced by iminosugars on K562 cells.
abstract: Iminosugars have gained a remarkable importance as new therapeutic agents since 1966. In this study, compounds A and B, two iminosugar analogs synthesized previously, showed an inhibition of the growth of K562 cells. They allowed cell cycle arrested at the G0/G1 phase, promoted apoptotic activities and also lowered the mitochondrial membrane potential. Further exploration of the apoptosis mechanism revealed that compound B significantly suppressed the expression of Hsp70, which is a major anti-apoptotic molecular chaperone. Significant decrease was also found in the expression of Akt, a serine/threonine-specific protein kinase with anti-apoptosis activities also known as protein kinase B (PKB). At mitochondria level in comparison with compound A, compound B brought a better promotion in the expression of pro-apoptotic protein Bad in Bcl-2 family. As a result of the promotion, the expression of anti-apoptotic protein Bcl-xL was down-regulated. Cytochrome c was released, activating the intrinsic signaling pathways of caspase and resulting in the occurrence of cascade reaction. In addition, compound B stimulated autophagy effectively by up-regulating Beclin 1, thus causing the conversion of LC3-I to LC3-II through Akt/mTOR signaling pathway. In summary, these results indicated that compounds A and B induced cell death through multiple pathways. The disclosed results not only provide an evidence of antitumor activity of iminosugars as a foundation for further studies, but also may find potential applications in chronic myeloid leukemia therapy as new heat shock protein inhibitors and autophagy inducer.
authors.affiliation: School of Life Sciences, Northeast Normal University, Changchun 130024, PR China; State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: School of Life Sciences, Northeast Normal University, Changchun 130024, PR China.
authors.forename: Yifa
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, PR China.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Northeast Normal University, Changchun 130024, PR China. Electronic address: taigh477@nenu.edu.cn.
authors.forename: Guihua
authors.initials: G
authors.lastname: Tai
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, PR China. Electronic address: xinshan@bjmu.edu.cn.
authors.forename: Xin-Shan
authors.initials: XS
authors.lastname: Ye
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050111:Imino Sugars / Q000494:pharmacology*; D020014:K562 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050111:Imino Sugars
keywords: Antitumor; Apoptosis; Autophagy; Cell cycle; Iminosugar; K562 cell line