1. Tiron and trolox potentiate the autophagic cell death induced by magnolol analog Ery5 by activation of Bax in HL-60 cells.
- Author
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Kumar S, Kumar A, Pathania AS, Guru SK, Jada S, Sharma PR, Bhushan S, Saxena AK, Kumar HM, and Malik F
- Subjects
- Amino Acid Chloromethyl Ketones pharmacology, Antineoplastic Agents chemical synthesis, Apoptosis drug effects, Apoptosis genetics, Autophagy genetics, Autophagy-Related Protein 12, Autophagy-Related Protein 7, Biphenyl Compounds chemical synthesis, Caspases genetics, Caspases metabolism, Drug Synergism, Gene Expression Regulation, Neoplastic drug effects, HL-60 Cells, Humans, Lignans chemical synthesis, Microtubule-Associated Proteins antagonists & inhibitors, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Phenols chemical synthesis, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-ret metabolism, Signal Transduction drug effects, Small Ubiquitin-Related Modifier Proteins antagonists & inhibitors, Small Ubiquitin-Related Modifier Proteins genetics, Small Ubiquitin-Related Modifier Proteins metabolism, Ubiquitin-Activating Enzymes antagonists & inhibitors, Ubiquitin-Activating Enzymes genetics, Ubiquitin-Activating Enzymes metabolism, bcl-2-Associated X Protein metabolism, 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt pharmacology, Antineoplastic Agents pharmacology, Autophagy drug effects, Biphenyl Compounds pharmacology, Chromans pharmacology, Lignans pharmacology, Phenols pharmacology, Proto-Oncogene Proteins c-ret genetics, bcl-2-Associated X Protein genetics
- Abstract
This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.
- Published
- 2013
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