Induction of cell cycle arrest by GL331 via triggering an ATM-dependent DNA damage response in HepG2 cells

Wang, Yajie; Chen, Xiaoguang; Xiao, Zhiyan; Liu, Geng-Tao; Sun, Hua

doi:10.1080/10286020.2012.684683

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…These studies raised a question: which is a better strategy, to activate or to inhibit ATM activity, in treating HCC patients? Recently, Wang et al revealed that GL331, a topoisomerase II inhibitor, activates autophosphorylation of ATM at S1981 and extends activations of DNA damage signaling pathways including TP53/p21 and Chk2/Cdc25A cascades to reach S phase arrest in HepG2 cells (Table 1) [146]. A small molecular inhibitor, CGK733, which targets kinase activity of ATM, can obviously reverse the resistance of HepG2 to taxol treatment (Tables 1 and 3) [147].…”

Section: The Impact Of Ddr Pathways On Hcc Developmentmentioning

confidence: 99%

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Yang

Chang

Wei

et al. 2014

BioMed Research International

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Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.

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Section: The Impact Of Ddr Pathways On Hcc Developmentmentioning

confidence: 99%

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Yang

Chang

Wei

et al. 2014

BioMed Research International

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“…Cell viability was assessed with MTT assay as previously described. 27 Various concentrations of CHB were added into wells and incubated for 72 hours. IC 50 value was defined as the drug concentration that inhibits 50% cell growth compared with the untreated controls and was calculated by Graphpad Prism 6.0 software.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was carried out as described previously. 27 The membrane was immunoblotted with mouse monoclonal antibody to caspase 3 (1:1,000), caspase 9 (1:500), mouse monoclonal antibody to Bax and Bcl-2 (1:500), rabbit polyclonal to Fas and FasL (1:500), rabbit polyclonal to β-actin (1:1,000), rabbit polyclonal to AIF (1:500) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), rabbit polyclonal to active capase 3 (1:1,000) (CST, Danvers, MA, USA), rabbit polyclonal to capase 8 (1:1,000), and rabbit polyclonal antibody to cytochrome c (1:500) (Bioworld Technology Inc., Nanjing, People’s Republic of China). The membranes were finally developed using enhanced chemiluminescence (Fuji Film, Tokyo, Japan) reagent (Applygen Technologies Inc.) and exposed to film according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway

Wang

Xiao

et al. 2015

DDDT

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Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.

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Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro

et al. 2013

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Ochratoxin A (OTA), one of the most abundant mycotoxin food contaminants, is classified as "possibly carcinogenic to humans." Our previous study showed that OTA could induce a G2 arrest in immortalized human gastric epithelium cells (GES-1). To explore the putative roles of oxidative DNA damage and the ataxia telangiectasia-mutated (ATM) pathways on the OTA-induced G2 arrest, the current study systematically evaluated the roles of reactive oxygen species (ROS) production, DNA damage, and ATM-dependent pathway activation on the OTA-induced G2 phase arrest in GES-1 cells. The results showed that OTA exposure elevated intracellular ROS production, which directly induced DNA damage and increased the levels of 8-OHdG and DNA double-strand breaks (DSBs). In addition, it was found that OTA treatment induced the phosphorylation of the ATM protein, as well as its downstream molecules Chk2 and p53, in response to DNA DSBs. Inhibition of ATM by the pharmacological inhibitor caffeine or siRNA effectively prevented the activation of ATM-dependent pathways and rescued the G2 arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G2 arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G2 arrest in GES-1 cells.

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Induction of cell cycle arrest by GL331 via triggering an ATM-dependent DNA damage response in HepG2 cells

Cited by 5 publications

References 21 publications

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway

Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro

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