Developing a Novel Indolocarbazole as Histone Deacetylases Inhibitor against Leukemia Cell Lines

Wang, Wenjing; Lv, Meng; Zhao, Xiaodong; Zhang, George

doi:10.1155/2015/675053

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…However, clinical trials concerning treatment strategies for leukemia have not achieved satisfactory outcomes, and new targets for treating leukemia are necessary. One of the best strategies for new anti-leukemia agents are carried out via induction of cell differentiation or apoptotic death in leukemia cells (3)(4)(5). Regulation and/or management of cell cycle progression and apoptosis are prominent approaches to anti-leukemia therapy (2,6).…”

Section: Introductionmentioning

confidence: 99%

CCY-1a-E2 induces G2/M phase arrest and apoptotic cell death in HL-60 leukemia cells through cyclin-dependent kinase 1 signaling and the mitochondria-dependent caspase pathway

et al. 2016

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Our previous study demonstrated that 2-[(3-methoxybenzyl)oxy]benzaldehyde (CCY-1a-E2) is a potent compound that acts against multiple human leukemia cell lines. CCY-1a-E2 was also shown to have efficacious anti‑leukemic activity in vivo. However, the molecular mechanism of action of CCY‑1a‑E2 attributed to its anticancer effect remains poorly understood. In the present study, CCY‑1a‑E2 suppressed cell viability in multiple leukemia cell lines (HL‑60, K562, KG‑1 and KG‑1a) via inhibition of cell proliferation, cell cycle arrest and induction of apoptosis. CCY‑1a‑E2 exhibited a marked toxic effect on HL‑60 cells and displayed low cytotoxicity in normal human peripheral blood mononuclear cells (PBMCs). Results from flow cytometric analysis indicated that CCY‑1a‑E2 promoted G2/M phase arrest and promoted apoptosis in the HL‑60 cells. CCY‑1a‑E2 treatment upregulated cyclin B, cyclin‑dependent kinase 1 (CDK1), cell division cycle 25C (cdc25C) and p21 protein expression. CCY‑1a‑E2 caused apoptotic cell death and DNA fragmentation as determined by 4',6‑diamidino‑2‑phenylindole (DAPI) staining and DNA gel electrophoresis. Elevated activities of caspase‑8, ‑9 and ‑3 were observed during CCY‑1a‑E2‑induced cell apoptosis; their specific inhibitors were found to block CCY‑1a‑E2‑induced apoptosis, respectively. Moreover, CCY‑1a‑E2 time‑dependently disrupted the mitochondrial membrane potential (ΔΨm), and it enhanced the protein levels of Fas/CD95, cytochrome c, Bax, cleaved PARP, as well as attenuated Bcl‑2 expression in the HL‑60 cells. Our results provide direct evidence that supports the future potential therapeutic application of CCY-1a-E2 in leukemia.

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Section: Introductionmentioning

confidence: 99%

CCY-1a-E2 induces G2/M phase arrest and apoptotic cell death in HL-60 leukemia cells through cyclin-dependent kinase 1 signaling and the mitochondria-dependent caspase pathway

et al. 2016

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“…Moreover, depletion of HDAC1 in hepatocellular cancer cells provoked a decrease in cell proliferation and an activation of autophagy-induced cell death [86]. Another HDACi, ZW2-1, also promoted both mitochondria-mediated apoptosis and the number of autophagy vesicles or the levels of LC3B-II in leukemia HL-60 cells [65].…”

Section: Hdaci (Classes I and Ii) Promote Autophagy Cell Death In Canmentioning

confidence: 99%

“…apoptosis and the number of autophagy vesicles or the levels of LC3B-II in leukemia HL-60 cells[65].…”

mentioning

confidence: 95%

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Peixoto

Grandvallet

Feugeas

et al. 2019

Cells

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Although autophagy is a well-known and extensively described cell pathway, numerous studies have been recently interested in studying the importance of its regulation at different molecular levels, including the translational and post-translational levels. Therefore, this review focuses on the links between autophagy and epigenetics in cancer and summarizes the. following: (i) how ATG genes are regulated by epigenetics, including DNA methylation and post-translational histone modifications; (ii) how epidrugs are able to modulate autophagy in cancer and to alter cancer-related phenotypes (proliferation, migration, invasion, tumorigenesis, etc.) and; (iii) how epigenetic enzymes can also regulate autophagy at the protein level. One noteable observation was that researchers most often reported conclusions about the regulation of the autophagy flux, following the use of epidrugs, based only on the analysis of LC3B-II form in treated cells. However, it is now widely accepted that an increase in LC3B-II form could be the consequence of an induction of the autophagy flux, as well as a block in the autophagosome-lysosome fusion. Therefore, in our review, all the published results describing a link between epidrugs and autophagy were systematically reanalyzed to determine whether autophagy flux was indeed increased, or inhibited, following the use of these potentially new interesting treatments targeting the autophagy process. Altogether, these recent data strongly support the idea that the determination of autophagy status could be crucial for future anticancer therapies. Indeed, the use of a combination of epidrugs and autophagy inhibitors could be beneficial for some cancer patients, whereas, in other cases, an increase of autophagy, which is frequently observed following the use of epidrugs, could lead to increased autophagy cell death.

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“…Inhibition of CD38 by CD38 shRNA or nicotinamide leads to accumulation of p62 and autophagosomes, suppressing lysosome fusion to autophagosomes [44]. Moreover, in indolocarbazole induced cell autophagy, CD38 expression and the LC3-II/LC3-I ratio are significantly elevated in response to ZW2-1 [45]. Subsequent studies showed that enzymatic activity of CD38 to produce NAADP plays an essential role in the following breakdown of the autophagic contents [19].…”

Section: The Positive Regulation Of Cd38 In Autophagymentioning

confidence: 99%

Dual Roles of CD38 in Autophagy

Wang¹,

Song²,

Wu³

et al. 2017

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CD38 is a versatile, ubiquitously expressed protein that was identified as a multifunctional enzyme. Recently, cumulating evidence has suggested that CD38 is involved in autophagy, which is an evolutionarily conserved lysosomal degradation and recycling system. Acting as a enzyme, CD38 utilizes nicotinamide adenine dinucleotide phosphate (NADP) to synthesize nicotinic acid adenine dinucleotide phosphate (NAADP), which acts as a key messenger for Ca 2+ -mobilizing in lysosome by targeting two-pore channels (TPCs) or transient receptor potential mucolipins (TRPMLs). Multiple studies have indicated that CD38 is involved in autophagy by modulating intracellular Ca 2+ signaling. However, the control of autophagy by CD38 signaling is the subject of two contrary views. The autophagosomes trafficking and fusion with lysosomes to form autolysosomes are crucial steps in autophagy. On the one hand, the available evidence indicates that lysosome trafficking and fusion to autophagosomes is positively modulated by CD38. On the other hand, overexpression of TPC2, which is positively modulated by CD38, was shown to promote the accumulation of autophagosomes, thus suppress autophagy. This review will reveal the interesting contrary dual roles of CD38 in autophagy, and critical insight into the molecular mechanisms of CD38 in autophagy regulation.

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Developing a Novel Indolocarbazole as Histone Deacetylases Inhibitor against Leukemia Cell Lines

Cited by 6 publications

References 25 publications

CCY-1a-E2 induces G2/M phase arrest and apoptotic cell death in HL-60 leukemia cells through cyclin-dependent kinase 1 signaling and the mitochondria-dependent caspase pathway

CCY-1a-E2 induces G2/M phase arrest and apoptotic cell death in HL-60 leukemia cells through cyclin-dependent kinase 1 signaling and the mitochondria-dependent caspase pathway

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

Dual Roles of CD38 in Autophagy

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