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Cell cycle arrest, apoptosis and autophagy induced by iminosugars on K562 cells
- Source :
- European Journal of Pharmacology. 731:65-72
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
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.
- Subjects :
- Membrane Potential, Mitochondrial
Pharmacology
Programmed cell death
Cell cycle checkpoint
Autophagy
G1 Phase
Antineoplastic Agents
Apoptosis
Cell Cycle Checkpoints
Cell cycle
Biology
Resting Phase, Cell Cycle
Imino Sugars
Cell biology
Gene Expression Regulation, Neoplastic
Heat shock protein
Humans
Signal transduction
K562 Cells
Protein kinase A
Protein kinase B
Subjects
Details
- ISSN :
- 00142999
- Volume :
- 731
- Database :
- OpenAIRE
- Journal :
- European Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....00fea6ddb3314e8cc873780b2c0ee768