Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway

Wu, Jianing; Ji, Zhiyong; Liu, Huailei; Liu, Yaohua; Han, Dayong; Chen, Shi; Shi, Changbin; Wang, Chunlei; Yang, Guang; Chen, Xiaofeng; Shen, Chen; Li, Huadong; Bi, Yunke; Zhang, Dongzhi; Zhao, Shen

doi:10.1016/j.toxlet.2013.03.019

Cited by 40 publications

(35 citation statements)

References 41 publications

(40 reference statements)

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“…Our previous studies have demonstrated the prominent effect of arsenic trioxide (ATO) in inhibiting the stemness of glioma stem cells (GSCs) by downregulating Notch signaling [7,8]. Raddeanin A (RA), an active extraction from the root of the traditional Chinese medicinal herb Anemone raddeana Regel [9], plays an important role in suppressing tumors (Fig.…”

Section: Introductionmentioning

confidence: 99%

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Peng

Wang

Shu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Raddeanin A (RA), an active pharmacological ingredient from Anemone raddeana Regel, plays an important role in tumor suppression. In this study, we assessed the potentially therapeutic effect of RA on glioblastoma and its underlying mechanisms. Methods: Cell viability was examined using the MTT assay. Invasive and migratory capacities were examined using Transwell and wound healing assays. Apoptosis was determined by Hoechst staining, flow cytometry, DCFH-fluorescent probe and immunohistochemical staining. Autophagy was detected by transmission electron microscopy and western blotting. A U251 glioma xenograft model was established to evaluate the effect of RA in vivo. Results: The data demonstrated that RA inhibited viability, and abrogated the invasive/migratory abilities of glioblastoma cells. In addition, RA induced apoptosis by reactive oxygen species (ROS)/ Jun N-terminal kinase (JNK) signaling in glioblastoma. Conversely, the antioxidant N-Acetyl-L-cysteine (NAC) and pan-caspase inhibitor z-VAD-fmk attenuated RA-induced apoptosis by scavenging ROS and inactivating caspase-3. Furthermore, the inhibition of autophagy by 3-MA exacerbated apoptosis through ROS generation and JNK phosphorylation. In vivo, RA exhibited a curative effect on U251-derived xenografts in nude mice. Conclusions: The results of this study suggest that RA suppressed the growth of glioblastoma, thus serving as a promising and potential strategy for glioblastoma chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Peng

Wang

Shu

et al. 2018

Cell Physiol Biochem

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“…Jianing Wu identified new therapeutic strategy for cancer stem-like cells and one of the mechanisms was that As 2 O 3 inhibited tumor proliferation through reducing the phosphorylation of AKT [32]. Ho-Shin Gwak studied the role of arsenic hexoxide (As 4 O 6 ) in inhibiting proliferation of glioblastoma cells, and they observed that As 4 O 6 decreased Akt phosphorylation in a dose-dependent manner in all malignant glioma cell lines used in the experiment [33].…”

Section: Discussionmentioning

confidence: 99%

Role of PTEN-Akt-CREB Signaling Pathway in Nervous System impairment of Rats with Chronic Arsenite Exposure

Gao

Sun

et al. 2015

Biol Trace Elem Res

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The nervous system is a target of arsenic toxicity. Phosphatase and tensin homologue deleted on chromosome 10/protein kinase B/cAMP-response element binding protein (PTEN/Akt/CREB) signaling pathway has been reported to be involved in maintaining normal function of the nervous system, modulating growth and proliferation of neurocyte, regulating neuron synaptic plasticity, and long-term memory. And many studies have demonstrated that expressions of PTEN, Akt, and CREB protein were influenced by arsenic, but it is not clear whether this signaling pathway is involved in the nervous system impairment of rats induced by chronic arsenite exposure, and we have addressed this in this study. Eighty male Sprague-Dawley (SD) rats were randomly divided into eight groups (n = 10 each), four groups exposed to NaAsO2 (0, 5, 10, and 50 mg/L NaAsO2 in drinking water) for 3 months, the other four groups exposed to NaAsO2 (0, 5, 10, 50 mg/L NaAsO2 in drinking water) for 6 months. Hematoxylin and eosin (HE) staining showed that chronic arsenite exposure induced varying degrees of damage in cerebral neurons. And arsenite exposure increased arsenic amount in serum and brain samples in a dose- and time-dependent manner. Moreover, the protein levels of PTEN and Akt in brain tissue were not significantly changed compared with the control group, but p-Akt, CREB, and p-CREB were all significantly downregulated in arsenite-exposed groups with a dose-dependent pattern. These results suggested that chronic arsenite exposure negatively regulated the PTEN-Akt-CREB signaling pathway, and dysfunction of the signaling pathway might be one of the mechanisms of nervous system impairment induced by chronic arsenite exposure.

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“…Furthermore, arsenic trioxide (ATO) is an FDA-approved drug used for treatment of patients with acute promyelocytic leukemia (APL). Preclinical studies have confirmed that ATO can induce cell apoptosis and inhibit tumor cell proliferation in a wide variety of solid tumors [32]. Therefore, it is very meaningful to investigate the involved mechanisms of arsenic toxicity.…”

Section: Discussionmentioning

confidence: 99%

Rac1 and Cdc42 Play Important Roles in Arsenic Neurotoxicity in Primary Cultured Rat Cerebellar Astrocytes

Liu

et al. 2015

Biol Trace Elem Res

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This study aimed to explore whether Rac1 and Cdc42, representative members of Ras homologue guanosine triphosphatases (Rho GTPases), are involved in neurotoxicity induced by arsenic exposure in rat nervous system. Expressions of Rac1 and Cdc42 in rat cerebellum and cerebrum exposed to different doses of NaAsO2 (Wistar rats drank 0, 2, 10, and 50 mg/L NaAsO2 water for 3 months) were examined. Both Rac1 and Cdc42 expressions increased significantly in a dose-dependent manner in cerebellum (P < 0.01) by Western blot and immunohistochemistry assay, but in cerebrum, Rac1 and Cdc42 expressions only in 2 mg/L exposure groups were significantly higher than those in control groups (P < 0.01). Five to 50 μM NaAsO2 decreased cell viability in a dose-dependent manner in primary cultured rat astrocytes, whereas 1 μM NaAsO2 increased the cell viability in these cells. Rac1 inhibitor, NSC23766, decreased NaAsO2-induced apoptosis and increased the cell viability in primary cultured rat cerebellar astrocytes exposed to 30 μM NaAsO2. Cdc42 inhibitor, ZCL278, increased cell viability in the cells exposed to 30 μM NaAsO2. Taken together, our current studies in vivo and in vitro indicate that activations of Rac1 and Cdc42 play a very important role in arsenic neurotoxicity in rat cerebellum, providing a new insight into arsenic neurotoxicity.

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Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway

Cited by 40 publications

References 41 publications

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Role of PTEN-Akt-CREB Signaling Pathway in Nervous System impairment of Rats with Chronic Arsenite Exposure

Rac1 and Cdc42 Play Important Roles in Arsenic Neurotoxicity in Primary Cultured Rat Cerebellar Astrocytes

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