Tetramethylpyrazine-mediated suppression of C6 gliomas involves inhibition of chemokine receptor CXCR4 expression

Yu, Keming; Pan, Xueke; Yang, Ying; Tian, Sijia; Zhang, Jing; Ge, Jian; Ambati, B.K.; Zhuang, Jing

doi:10.3892/or.2012.1866

Cited by 30 publications

(29 citation statements)

References 20 publications

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“…1B, C). These results are consistent with those of previous reports, showing that TMP effectively down-regulates CXCR4 expression in C6 cells [15], [26].…”

Section: Resultssupporting

confidence: 94%

Inhibition of Angiogenesis, Fibrosis and Thrombosis by Tetramethylpyrazine: Mechanisms Contributing to the SDF-1/CXCR4 Axis

et al. 2014

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BackgroundTetramethylpyrazine (TMP) is one of the active ingredients extracted from the Chinese herb Chuanxiong, which has been used to treat cerebrovascular and cardiovascular diseases, pulmonary diseases and cancer. However, the molecular mechanisms underlying the actions of TMP have not been fully elucidated. In a previous study we showed that TMP-mediated glioma suppression and neural protection involves the inhibition of CXCR4 expression. The SDF-1/CXCR4 axis plays a fundamental role in many physiological and pathological processes. In this study, we further investigated whether the regulation of the SDF-1/CXCR4 pathway is also involved in the TMP-mediated inhibition of neovascularization or fibrosis and improvement of microcirculation.Methodology/Principal FindingsUsing a scratch-wound assay, we demonstrated that TMP significantly suppressed the migration and tubule formation of the human umbilical vein endothelial cell line ECV304 in vitro. The expression of CXCR4 in ECV304 cells is notably down-regulated after TMP treatment. In addition, TMP significantly suppresses corneal neovascularization in a rat model of corneal alkali burn injury. The expression of CXCR4 on days 1, 3 and 7 post-injury was determined through RT-PCR analysis. Consistent with our hypotheses, the expression of CXCR4 in the rat cornea is significantly increased with alkali burn and dramatically down-regulated with TMP treatment. Moreover, TMP treatment significantly attenuates bleomycin-induced rat pulmonary fibrosis, while immunofluorescence shows a notably decreased amount of CXCR4-positive cells in the TMP-treated group. Furthermore, TMP significantly down-regulates the expression of CXCR4 in platelets, lymphocytes and red blood cells. Whole-blood viscosity and platelet aggregation in rats are significantly decreased by TMP treatment.ConclusionsThese results show that TMP exerts potent effects in inhibiting neovascularization, fibrosis and thrombosis under pathological conditions; thus, the underlying mechanism of TMP might partially contribute to the down-regulation of CXCR4.

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“…1B, C). These results are consistent with those of previous reports, showing that TMP effectively down-regulates CXCR4 expression in C6 cells [15], [26].…”

Section: Resultssupporting

confidence: 94%

Inhibition of Angiogenesis, Fibrosis and Thrombosis by Tetramethylpyrazine: Mechanisms Contributing to the SDF-1/CXCR4 Axis

et al. 2014

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“…Accordingly, the cell cycle profile data in the current study demonstrated that TMP treatment resulted in arrest of WERI-Rb1 cells in the G1 phase when the cells were cultured to a high density. These cell cycle data are similar to the results of our previous study (18), revealing that TMP only affects the cell cycle of glioma C6 cells at 100% confluency. However, the different cell type the previous study produced differing results, with TMP inducing arrest in the S phase in C6 cells, and significantly reducing the G1 and G2 populations compared with control cells (18).…”

Section: Discussionsupporting

confidence: 91%

“…These cell cycle data are similar to the results of our previous study (18), revealing that TMP only affects the cell cycle of glioma C6 cells at 100% confluency. However, the different cell type the previous study produced differing results, with TMP inducing arrest in the S phase in C6 cells, and significantly reducing the G1 and G2 populations compared with control cells (18). Therefore, TMP may reduce CXCR4 expression, and subsequently arrest the cell cycle at the G1 phase, eventually inhibiting tumor cell proliferation in retinoblastoma.…”

Section: Discussionsupporting

confidence: 91%

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Tetramethylpyrazine-mediated regulation of CXCR4 in retinoblastoma is sensitive to cell density

Yang

et al. 2017

Molecular Medicine Reports

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Retinoblastoma is the most common ocular tumor in children, and it causes extensive damage. Current treatment options for retinoblastoma include surgery, chemotherapy, radiotherapy and cryotherapy. However, the majority of chemotherapy medicines cause complications and side effects that lead to severe impairment of patient health. Previous studies have reported that tetramethylpyrazine (TMP), which is an extract of the Chinese herbal medicine Chuanxiong, reduces the risk of multidrug resistance in chemotherapy and inhibits the proliferation and metastasis of various types of cancer cells. However, the underlying molecular mechanism of TMP in retinoblastoma remains unclear. The current study demonstrated that C-X-C chemokine receptor type 4 (CXCR4) was expressed in WERI-Rb1 cells and in retinoblastoma. Using reverse transcription-quantitative polymerase chain reaction and western blotting techniques, the current study demonstrated that TMP significantly downregulated the expression of CXCR4 in WERI-Rb1 cells cultured at high density, whereas it had a minor effect in low-density WERI-Rb1 cells; additionally, this effect occurred in a time-dependent manner. TMP inhibited the proliferation of WERI-Rb1 cells as effectively as a CXCR4 antagonist, AMD3100, consistent with a role of CXCR4 in cancer development. Notably, TMP did not affect the cell cycle of cells cultured at low density (1×105 cells/ml), whereas it induced G1-phase arrest in high-density cells (7.5×105 cells/ml; P<0.05). In addition, the expression of CXCR4 in primary rat retinal neurocytes was significantly downregulated by TMP treatment, and this treatment protected primary rat retinal neurocytes from H2O2-induced damage. Thus, the results of this study indicate that TMP is a potential candidate for use in treatment of retinoblastoma, and also provides novel insights into the mechanisms of the anti-cancer and neuroprotective effects of this extract.

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“…[14][15][16][17][18]29 Clinical studies also suggest that TMP shows promise as complementary therapy for various Images were captured by a confocal laser scanning microscope (Zeiss LSM 510). F-actin content was quantified using Zeiss LSM 510 Examiner software and normalized by cell number to evaluate stress fiber formation.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine Attenuates Transdifferentiation of TGF-β2–Treated Human Tenon's Fibroblasts

Cai

Yang

Chen

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Cai X, Yang Y, Chen P, et al. Tetramethylpyrazine attenuates transdifferentiation of TGF-b2-treated human Tenon's fibroblasts. Invest Ophthalmol Vis Sci. 2016;57:4740-4748. DOI:10.1167/iovs.16-19529 PURPOSE. To investigate the pharmacologic effect of tetramethylpyrazine (TMP) on human Tenon's fibroblasts (HTFs), the cells implicated in scarring after filtration surgery. METHODS.Transforming growth factor-b2 (TGF-b2) was used to stimulate a fibrotic phenotype in primary HTFs, and the influence of TMP on the fibrotic phenotype was assessed. Cell proliferation and cell cycle regulation were profiled. Immunofluorescence staining tracked proliferating cell nuclear antigen (PCNA) expression. Transwell assays monitored cell migration. Flow cytometry measured TMP toxicity. In addition, in TGF-b2-treated HTFs, Western blot and immunofluorescence were employed to assess the expression of a-smooth muscle actin (a-SMA). The TMP-mediated activity on cytoskeletal arrangements and extracellular matrix (ECM) accumulation in HTFs was evaluated using actin polymerization and Western blot assays. Moreover, TGF-b-dependent activation of Smad3 and p38 was examined by Western blot analysis. RESULTS.In TGF-b2-treated HTFs, TMP reduced proliferation and migration but did not induce apoptosis. Moreover, TMP attenuated expression of a-SMA and suppressed stress fiber formation stimulated by profibrotic cytokine; it also counteracted TGF-b2-induced cytoskeletal rearrangements, morphologic changes, and ECM accumulation. Smad3 and p38 mitogenactivated protein kinase (MAPK) signaling were downstream of the TMP-sensitive effect.CONCLUSIONS. Tetramethylpyrazine counteracts TGF-b2-mediated myofibroblast transdifferentiation and attenuates ECM component deposition and cell proliferation in HTFs, implicating TMP as a potential antifibrosis agent in glaucoma filtration surgery.

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Tetramethylpyrazine-mediated suppression of C6 gliomas involves inhibition of chemokine receptor CXCR4 expression

Cited by 30 publications

References 20 publications

Inhibition of Angiogenesis, Fibrosis and Thrombosis by Tetramethylpyrazine: Mechanisms Contributing to the SDF-1/CXCR4 Axis

Inhibition of Angiogenesis, Fibrosis and Thrombosis by Tetramethylpyrazine: Mechanisms Contributing to the SDF-1/CXCR4 Axis

Tetramethylpyrazine-mediated regulation of CXCR4 in retinoblastoma is sensitive to cell density

Tetramethylpyrazine Attenuates Transdifferentiation of TGF-β2–Treated Human Tenon's Fibroblasts

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