Role of the ROS/AMPK signaling pathway in tetramethylpyrazine-induced apoptosis in gastric cancer cells

Yi, Bo‐Rim; Liu, Dan; He, Ming-Ming; Li, Qiyun; Liu, Tiande; Shao, Jianghua

doi:10.3892/ol.2013.1403

Cited by 45 publications

(29 citation statements)

References 28 publications

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“…The results revealed that 8e could induce FaDu cells' apoptosis in a dose-dependent manner. This was consistent with other reports showing TMP and its derivatives could induce apoptosis of cancer cells [22][23][24].…”

Section: Apoptosis Analysis By Annexin V-fitc/pi Stainingsupporting

confidence: 94%

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

Wang

Hong

et al. 2019

Molecules

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Bivalent and polyvalent inhibitors can be used as antitumor agents. In this experiment, eight ligustrazine dimers and seven ligustrazine tetramers linked by alkane diamine with different lengths of carbon chain lengths were synthesized. After screening their antiproliferation activities against five cancer cell lines, most ligustrazine derivatives showed better cytotoxicity than the ligustrazine monomer. In particular, ligustrazine dimer 8e linked with decane-1,10-diamine exhibited the highest cytotoxicity in FaDu cells with an IC50 (50% inhibiting concentration) value of 1.36 nM. Further mechanism studies suggested that 8e could induce apoptosis of FaDu cells through the depolarization of mitochondrial membrane potential and S-phase cell cycle arrest. Inspired by these results, twenty-seven additional small molecule heterocyclic dimers linked with decane-1,10-diamine and nine cinnamic acid dimers bearing ether chain were synthesized and screened. Most monocyclic and bicyclic aromatic systems showed highly selective anti-proliferation activity to FaDu cells and low toxicity to normal MCF 10A cells. The structure-activity relationship revealed that the two terminal amide bonds and the alkyl linker with a chain length of 8–12 carbon were two important factors to maintain its antitumor activity. In addition, the ADMET calculation predicted that most of the potent compounds had good oral bioavailability.

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Section: Apoptosis Analysis By Annexin V-fitc/pi Stainingsupporting

confidence: 94%

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

Wang

Hong

et al. 2019

Molecules

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“…The anti-cancer properties of TMP have been observed in many types of cancer. It was shown that TMP induced ROS generation and activated mitochondrial-mediated apoptotic pathway in human gastric cancer [20]. TMP may inhibit proliferation of lymphocytic leukemia and gastric carcinoma cells [21, 22].…”

Section: Discussionmentioning

confidence: 99%

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

et al. 2016

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The mitochondrial respiratory chain, including mitochondrial complex II, has emerged as a potential target for cancer therapy. In the present study, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), DT-010, was synthesized. Our results showed that DT-010 is more potent than its parental compounds separately or in combination, in inhibiting the proliferation of MCF-7 and MDA-MB-231 cells by inducing cytotoxicity and promoting cell cycle arrest. It also inhibited the growth of 4T1 breast cancer cells in vivo. DT-010 suppressed the fundamental parameters of mitochondrial function in MCF-7 cells, including basal respiration, ATP turnover, maximal respiration. Treatment with DT-010 in MCF-7 and MDA-MB-231 cells resulted in the loss of mitochondrial membrane potential and decreased ATP production. DT-010 also promoted ROS generation, while treatment with ROS scavenger, NAC (N-acetyl-L-cysteine), reversed DT-010-induced cytotoxicity. Further study showed that DT-010 suppressed succinate-induced mitochondrial respiration and impaired mitochondrial complex II enzyme activity indicating that DT-010 may inhibit mitochondrial complex II. Overall, our results suggested that the antitumor activity of DT-010 is associated with inhibition of mitochondrial complex II, which triggers ROS generation and mitochondrial dysfunction in breast cancer cells.

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“…Tetramethylpyrazine (TMP) (2,3,5,6-tetramethylpyrazine; C 8 H 12 N 2 ) is one of the bioactive ingredients extracted from the rhizome of the Chinese herb Ligusticum. Studies have demonstrated that TMP has potent inhibitory effects on a variety of tumors through affecting the proliferation and migration of tumor cells (10)(11)(12). In our previous study, TMP was found to inhibit the growth of HL-60 cells by inducing their differentiation (13).…”

Section: Introductionmentioning

confidence: 88%

Tetramethylpyrazine inhibits the proliferation of acute lymphocytic leukemia cell lines via decrease in GSK-3β

et al. 2015

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Tetramethylpyrazine (TMP) has been proven to be an anticancer agent in many studies. However, its effectiveness in acute lymphoblastic leukemia (ALL) and its molecular mechanisms are still unclear. The present study aimed to evaluate the effect of TMP against Jurkat and SUP-B15 ALL cell lines and to investigate the possible detailed mechanism of action of TMP. A Cell Counting Kit-8 (CCK-8) assay was employed to examine the proliferation of Jurkat and SUP-B15 cells. Flow cytometric analysis was conducted to detect the cell cycle distribution and apoptotic rate. The expression of total glycogen synthase kinase-3β (GSK-3β), cox-2, survivin, bcl-2 and p27 RNA and protein levels was detected by quantitative real-time PCR and western blot assay, respectively. Additionally, western blot analysis was used to determine the whole-cell and nuclear protein levels of GSK-3β downstream transcription factors, NF-κB (p65) and c-myc. TMP inhibited the proliferation of Jurkat and SUP-B15 cells in a dose- and time-dependent manner, with IC₅₀ values of 120 and 200 µg/ml, respectively at 48 h. TMP induced the apoptosis of Jurkat and SUP-B15 cells and synergistically blocked cell cycle progression at the G0/G1 phase. Cells treated with TMP exhibited significantly attenuated GSK-3β, NF-κB (p65) and c-myc expression, followed by downregulation of bcl-2, cox-2 and survivin and an upregulation of p27. The results showed that TMP induced apoptosis and caused cell cycle arrest in Jurkat and SUP-B15 cells through the downregulation of GSK-3β, which may have further prevented the induced translocation of NF-κB and c-myc from the cytoplasm to the nucleus.

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Role of the ROS/AMPK signaling pathway in tetramethylpyrazine-induced apoptosis in gastric cancer cells

Cited by 45 publications

References 28 publications

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

Novel Homo-Bivalent and Polyvalent Compounds Based on Ligustrazine and Heterocyclic Ring as Anticancer Agents

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

Tetramethylpyrazine inhibits the proliferation of acute lymphocytic leukemia cell lines via decrease in GSK-3β

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