Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo

Yang, Xi; Yang, Baixia; Cai, Jing; Zhang, Chi; Qu, Zhipeng; Xu, Liping; Qin, Qin; Zhu, Hongcheng; Ma, Jianxin; Tao, Guangzhou; Cheng, Hongyan; Sun, Xinchen

doi:10.4161/cbt.26426

Cited by 62 publications

(40 citation statements)

References 19 publications

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“…Furthermore, by exposing ESCC cells to hypoxia, we demonstrated that STAT3/HIF-1α/VEGF signaling pathway is involved in the radioresistance of ESCC, and stattic reverses the radioresistance by blocking STAT3/HIF-1α/VEGF signaling pathway. These results are in agreement with recent data that berberine increased the radiosensitivity of ESCC cells and xenografts via the inhibition of HIF-1α and VEGF expression [24].…”

Section: Discussionsupporting

confidence: 93%

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma

Zhang

et al. 2014

Tumor Biol.

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The radioresistance of esophageal squamous cell carcinoma (ESCC) remains an obstacle for the effective radiotherapy of ESCC. This study aimed to investigate the radiosensitization of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor stattic. ECA109, TE13, and KYSE150 cell lines were exposed to hypoxia and treated with stattic or radiation, alone or in combination. Cell proliferation, colony formation, apoptosis, and double-stranded DNA breaks (DSBs) were examined. In addition, ECA109 cells were xenografted into nude mice and treated with radiation and/or stattic. The levels of STAT3, p-STAT3, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in ESCC cells and xenografts were detected by Western blot and immunohistochemical analysis. Our results showed that stattic efficiently radiosensitized ESCC cells and xenografts, especially under hypoxia. Moreover, stattic inhibited STAT3 activation and downregulated HIF-1α and VEGF expression. In conclusion, stattic confers radiosensitivity in ESCC cells in vitro and in vivo and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting.

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Section: Discussionsupporting

confidence: 93%

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma

Zhang

et al. 2014

Tumor Biol.

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“…The oxygen occurred during radiotherapy generates free oxygen radicals that induce DNA damage and kill tumor cells. 8,9 A hypoxic environment can stimulate the selection of locally or systemically aggressive tumor cell phenotypes by increased genomic instability, mutation and downregulation of DNA repair. 10 Under hypoxia, the homologous recombination (HR) pathway involved in DSB repair is compromised.…”

Section: Introductionmentioning

confidence: 99%

Novel poly (ADP-ribose) polymerase inhibitor, AZD2281, enhances radiosensitivity of both normoxic and hypoxic esophageal squamous cancer cells

Qin

Lü

et al. 2015

Dis Esophagus

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Radiotherapy plays an important role in the treatment of esophageal squamous cell carcinoma (ESCC). However, the outcome of radiotherapy in ESCC remains unsatisfactory because esophageal squamous cancer cells, particularly those under hypoxic condition, exhibit radioresistance. The aim of this study was to determine whether or not AZD2281, a potent poly (ADP-ribose) polymerase (PARP) inhibitor, could enhance the radiation sensitivity of two ESCC cell lines, namely ECA109 and TE13. The radiosensitizing effect of AZD2281 was evaluated on the basis of cell death, clonogenic survival and tumor xenograft progression. AZD2281 alone was slightly toxic to ESCC cell lines. Apoptosis was increased and clonogenic survival was decreased in both cell lines when AZD2281 was combined with ionizing radiation (IR) under normoxic condition. AZD2281 enhanced IR-induced apoptosis to a more significant level under chronic hypoxic condition (0.2% O(2), 48 hour) than under normoxic condition. AZD2281 also slightly enhanced clonogenic cell death under chronic hypoxic condition compared with that under normoxic condition. This result could be associated with increased radiation-induced DNA double-strand breaks (DSB), decreased DSB repair and increased apoptosis of ESCC cells. Furthermore, homologous recombination (HR) protein Rad51 expression and focus formation were decreased in ESCC cells exposed to moderate chronic hypoxic condition (0.2% O(2), 48 hour); this result indicated that chronic hypoxic ESCC cells were HR deficient, possibly causing contextual synthetic lethality with PARP inhibitor in radiation sensitization. AZD2281 was also a radiation sensitizer in ESCC tumor xenograft models. Hence, in vitro and in vivo findings provide evidence that AZD2281 potently sensitizes ESCC cells to X-ray irradiation. The selective cell killing of HR-defective hypoxic cells contributes to radiosensitization by PARP inhibitor in ESCC cells under hypoxic condition.

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“…Hypoxia in tumors results from the imbalance between the increased oxygen consumption caused by extensive growth of tumor cells and poor oxygen delivery by disorganized tumor blood vessels (42). Drugs that target the hypoxia associated with resistance to radiation have had promising results (43). In the current study, paeonol caused marked downregulation of HIF-1α and VEGF in a dose-dependent manner with all tested radiation doses.…”

Section: Discussionmentioning

confidence: 51%

Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor

Zhou¹,

Sun²,

Cheng

2017

Experimental and Therapeutic Medicine

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Abstract. Radiotherapy is a vital and effective method to treat solid tumors. However, in many tumor types, development of resistance of cancer cells and cytotoxicity in normal tissues presents a major therapeutic problem. It is therefore crucial to identify and develop novel sensitizing agents that may improve the response to radiation therapy without causing any adverse effects. The present study aimed to investigate whether paeonol, a bioactive flavonoid, was able to confer sensitivity to radiation in human ovarian cancer cells. The human ovarian cancer cell lines SKOV-3 and OVCAR-3 were exposed to varying doses of radiation (2, 4 or 6 Gy) in the presence or absence of paeonol (25, 50 or 100 µM). Radiosensitivity was assessed by measuring cell viability using a CCK-8 assay and Annexin V/PI staining. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), proteins of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and apoptotic pathway proteins [caspase-3, Bcl-2-associated death promoter, B-cell lymphoma (Bcl)-2, Bcl-2-associated X and Bcl-extra large (Bcl-xL)] were also assessed. Paeonol treatment enhanced apoptosis of SKOV-3 and OVCAR-3 cells that were exposed to radiation. The expression of Bcl-2 and Bcl-xL were markedly upregulated in these cells. Treatment with paeonol concentrations of 50 and 100 µM caused a significant downregulation of VEGF, HIF-1α and PI3K/Akt pathway proteins. Paeonol effectively enhanced the sensitivity of ovarian cancer cells to radiation by significantly altering regulation of the proteins of the PI3K/Akt pathway, in addition to downregulating VEGF and HIF-1α.

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Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo

Cited by 62 publications

References 19 publications

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma

Novel poly (ADP-ribose) polymerase inhibitor, AZD2281, enhances radiosensitivity of both normoxic and hypoxic esophageal squamous cancer cells

Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor

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