Tetramethylpyrazine potentiates arsenic trioxide activity against HL-60 cell lines

Wu, Yuni; You-hua, XU; Shen, Yali; Wang, Cuicui; Guo, Gaili; Hu, Tiantian

doi:10.1590/s0100-879x2012007500017

Cited by 11 publications

(10 citation statements)

References 24 publications

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“…This is consistent with previous reports using ATRA with or without TNF or 12-O-tetradecanoyl phorbol-13-acetate (Bartova et al 2000, Liu et al 2004b, Meyerson et al 1997, Ramakrishnan et al 1998, Wu et al 2012, Yamada et al 2000). Telomerase activity was significantly further reduced in granulocytes by pre-exposure to either PCB congener and in monocytes be pre- and continuous exposure during differentiation to this congeners.…”

Section: Discussionsupporting

confidence: 93%

Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

Xing

Senthilkumar

Schnoor

et al. 2015

Environ Sci Pollut Res

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PCBs are persistent organic pollutants with carcinogenic, immune- and developmental toxicity. This suggests that they may interfere with normal cell maturation. Cancer and stem/progenitor cells have telomerase activity to maintain and protect the chromosome ends, but lose this activity during differentiation. We hypothesized that PCBs interfere with telomerase activity and the telomere complex thereby disturbing cell differentiation and stem/progenitor cell function. HL-60 cells are cancer cells that can differentiate to granulocytes and monocytes. We exposed HL-60 cells to the PCB126 (dioxin-like) and PCB153 (non-dioxin-like) 6 days before and during 3 days of differentiation. The differentiated cells showed G0/G1 phase arrest and very low telomerase activity. hTERT and hTR, two telomerase-related genes, were down-regulated. The telomere shelterins TRF1, TRF2, and POT were upregulated in granulocytes, TRF2 was up- and POT1 downregulated in monocytes. Both PCBs reduced telomerase activity in undifferentiated cells and further reduced telomerase activity in differentiated cells, but had only small effects on the differentiation and telomere-related genes. Long term treatment of undifferentiated HL-60 cells with PCB126 produced a downregulation of telomerase activity and decrease of hTERT, hTR, TRF1, and POT1 gene expression. With PCB153 the effects were less pronounced and some shelterin genes were increased after 30 days exposure. With each PCB no differentiation of cells was observed and cells continued to proliferate despite reduced telomerase activity, resulting in shortened telomeres after 30 days of exposure. These results indicate cell type and PCB congener specific effects on telomeres/telomerase-related genes and, although PCBs do not seem to strongly affect differentiation, they could influence the longevity of stem or progenitor cells through telomere attrition with potential long-term consequences for health.

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Section: Discussionsupporting

confidence: 93%

Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

Xing

Senthilkumar

Schnoor

et al. 2015

Environ Sci Pollut Res

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“…The biological activities of TMP showed cell selectivity. Our present findings indicated that TMP protected HK-2 cells against arsenic-induced apoptosis and on the other hand, TMP was also reported to promote arsenic trioxide toxicity and inhibit proliferation in human promyelocytic leukemia cell line HL-60 (Wu et al 2012). Such a cell specificity of pro-apoptotic or anti-apoptotic effect of TMP was also observed in hepatocytes (Zhang et al 2013).…”

Section: Discussionsupporting

confidence: 59%

Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death

et al. 2014

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Although kidney is a target organ of arsenic cytotoxicity, the underlying mechanisms of arsenic-induced nephrotoxicity remain poorly understood. As tetramethylpyrazine (TMP) has recently been found to be a renal protectant in multiple kidney injuries, we hypothesize that TMP could suppress arsenic nephrotoxicity. In this study, human renal proximal tubular epithelial cell line HK-2 was used to elucidate the precise mechanisms of arsenic nephrotoxicity as well as the protective mechanism of TMP in these cells. Sodium arsenite exposure dramatically increased cellular reactive oxygen species (ROS) production, decreased levels of cellular glutathione (GSH), decreased cytochrome c oxidase activity and mitochondrial membrane potential, which indicated mitochondrial dysfunction. On the other hand, sodium arsenite activated pro-inflammatory signals, including β-catenin, nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor alpha and cyclooxygenase-2 (COX-2). Small molecule inhibitors of NF-κB and p38 MAPK blocked arsenic-induced COX-2 expression, suggesting arsenic-induced COX-2 upregulation was NF-κB- and p38 MAPK-dependent. Finally, sodium arsenite induced autophagy in HK-2 cells at early phase (6 h) and the subsequent apoptosis at 24 h. Treatment by TMP or by the antioxidant N-acetylcysteine decreased arsenic-induced ROS production, enhanced GSH levels, prevented mitochondria dysfunction and suppressed the activation of pro-inflammatory signals and the development of autophagy and apoptosis. Our results suggested that TMP may be used as a new potential therapeutic agent to prevent arsenic-induced nephrotoxicity by suppressing these pathological processes.

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“…Furthermore, such protection was performed by preventing As -triggered activation of the intrinsic apoptotic pathway. Interestingly, TMP was also found to inhibit proliferation of human promyelocytic leukemia cell line HL-60 (Wu et al 2012). …”

Section: Discussionmentioning

confidence: 99%

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2015

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Our recent study demonstrated that sodium arsenite at a clinically relevant dose induced nephrotoxicity in human renal proximal tubular epithelial cell line HK-2, which could be inhibited by natural product 2,3,5,6-Tetramethylpyrazine (TMP) with antioxidant activity. The present study demonstrated that arsenic exposure resulted in protein and enzymatic induction of heme oxygenase-1 (HO-1) in dose- and time-dependent manners in HK-2 cells. Blocking HO-1enzymatic activity by Zinc protoporphyrin (ZnPP) augmented arsenic-induced apoptosis, ROS production and mitochondrial dysfunction, suggesting a critical role for HO-1 as a renal protectant in this procession. On the other hand, TMP, upstream of HO-1, inhibited arsenic-induced ROS production and ROS-dependent HO-1 expression. TMP also prevented mitochondria dysfunction and suppressed activation of the intrinsic apoptotic pathway in HK-2 cells. Our results revealed that the regulation of arsenic-induced HO-1 expression was performed through multiple ROS-dependent signal pathways and the corresponding transcription factors, including p38 MAPK and JNK (but not ERK), AP-1, Nrf2 and NF-κB. TMP inhibited arsenic-induced activations of JNK, p38 MAPK, ERK, AP-1 and Nrf2 and block HO-1 protein expression. The present study, furthermore, demonstrated arsenic-induced expression of Arsenic response protein 2 (ARS2) that was regulated by p38 MAPK, ERK and NF-κB. To our knowledge, this is the first report showing that ARS2 involved in arsenic-induced nephrotoxicity while TMP pretreatment prevented such an up-regulation of ARS2 in HK-2 cells. Given ARS2 and HO-1 sharing the similar regulation mechanism, we speculated that ARS2 might also mediate cell survival in this procession. In summary, our study highlighted a role of HO-1 in the protection against arsenic-induced cytotoxicity downstream from the primary targets of TMP and further indicated that TMP may be used as a potential therapeutic agent in the treatment of arsenic-induced nephrotoxicity.

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Tetramethylpyrazine potentiates arsenic trioxide activity against HL-60 cell lines

Cited by 11 publications

References 24 publications

Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

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