R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II

Zhu, Hong; Huang, Min; Yang, Fan; Chen, Yi; Miao, Ze‐Hong; Qian, Xuhong; Xu, Yufang; Qin, Yuxin; Luo, Haibin; Shen, Xu; Geng, Meiyu; Cai, Yujun; Ding, Jian

doi:10.1158/1535-7163.mct-06-0584

Cited by 77 publications

(60 citation statements)

References 40 publications

(35 reference statements)

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“…These findings suggest that G226 may target Topo II to inhibit cancer cell growth. Although it is well known that many Topo II-targeted anticancer drugs often cause DNA strand breaks [21] , Topo II poisons are not the only ones to induce DNA damage. Indeed, the patterns of DNA breaks induced by Topo II inhibitors are similar to other stimuli such as ROS [22] .…”

Section: Discussionmentioning

confidence: 99%

“…We were thus encouraged to address effects of G226-driven Topo II inhibition and understand whether it plays a vital role in G226-mediated DNA damage and apoptosis. Therefore, we examined the HL-60/MX2 cell line, which is deficient in Topo II and exhibits resistance to Topo II inhibitors, such as mitoxantrone, VP16, VM-26, and R16 [20,21] . This cell line also displayed resistance to VP-16 and ADR; the RF values were 86.9 and 26.4, respectively.…”

Section: Discussionmentioning

confidence: 99%

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G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation

Zhang

Che³

et al. 2014

Acta Pharmacol Sin

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Aim: G226 is a novel derivative of epipolythiodioxopiperazines with potent inhibitory activity against cancer cells. Here, we sought to identify potential targets involved in the anti-cancer activity of G226. Methods: Cell proliferation assay was conducted in a panel of 12 human cancer cell lines. The activities of topoisomerase I (Topo I) and Topo II were studied using supercoiled pBR322 DNA relaxation and kDNA decatenation assays. ROS production was assessed with probes DCFH-DA and H&E. Western blot analysis and flow cytometry were used to examine DNA damage, apoptosis and cell cycle changes. Results: G226 displayed potent cytotoxicity in the 12 human cancer cell lines with a mean IC 50 value of 92.7 nmol/L. This compound (1-100 µmol/L) selectively inhibited the activity of Topo II, and elevated the expression of phosphorylated-H2AX in a dose-dependent manner. In Topo II-deficient HL60/MX2 cells, however, G226-induced DNA damage, apoptosis and cytotoxicity were only partially reduced, suggesting that Topo II was not essential for the anti-tumor effects of G226. Furthermore, G226 (0.125-2 µmol/L) dosedependently elevated the intracellular levels of H 2 O 2 and O 2 · in the cancer cells, and pretreatment with GSH, NAC or DTT not only blocked G226-induced intracellular accumulation of ROS, but also abrogated G226-mediated phosphorylation of H2AX, apoptosis and cytotoxicity. Conclusion: G226-mediated ROS production contributes to the anti-cancer activity of this compound.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation

Zhang

Che³

et al. 2014

Acta Pharmacol Sin

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“…Previous studies reported several amonafide analogues that show stronger antitumor effects than amonafide (25,26). In our previous study, a novel amonafide analogue B1 was designed to aim at improving the antitumor efficiency and, in particular, to alleviate the toxicity of the parent compound amonafide (15).…”

Section: Discussionmentioning

confidence: 99%

B1, a Novel Amonafide Analogue, Overcomes the Resistance Conferred by Bcl-2 in Human Promyelocytic Leukemia HL60 Cells

Liang

Xu²,

Xu³

et al. 2010

Molecular Cancer Research

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In the course of screening for novel anticancer compounds, B1 [N-(2-(dimethylamino)ethyl)-2-aminothiazonaphthalimide], a novel amonafide analogue, was generated as a new anticancer candidate. In the present study, B1 displayed stronger antitumor effects than amonafide in HL60 cells. We further examined whether B1 overcomes the resistance conferred by Bcl-2, as overcoming the resistance conferred by Bcl-2 represents an attractive therapeutic strategy against cancer. Our viability assay showed that B1 overcomes the resistance conferred by Bcl-2 in human promyelocytic leukemia HL60 cells. Various apoptosis assessment assays showed that B1 overcomes the resistance conferred by Bcl-2 in HL60 cells by inducing apoptosis. Noticeably, we elucidated the marked downregulation of 14-3-3s protein by B1, indicating that B1 overcomes the resistance conferred by Bcl-2 in HL60 cells via 14-3-3s. The analysis of chromatin immunoprecipitation assay indicated that MBD2 was associated with the methylated 14-3-3s promoter-associated CpG island and thus interfered with transcriptional activity of the methylated promoter. Furthermore, knockdown of MBD2, using siRNA transfection, inhibited B1-induced apoptosis and overcame the resistance conferred by Bcl-2. Accordingly, these data showed the involvement of MBD2 in B1-induced apoptosis and overcoming the resistance conferred by Bcl-2, which suggested that MBD2 might guide the development of future anticancer agents.

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“…The primary neutrophils with a purity of >98% were either used immediately or cultured in a humidified 5% CO 2 incubator. H22 murine hepatoma cell line (syngeneic to the Kunming strain of mice) was provided by Prof. Xiaoguang Chen (Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China) and passaged in vivo in the Kunming mice with ascitic fluid (27,28).…”

Section: Methodsmentioning

confidence: 99%

“…Kunming mice were originated from outbred group of Swiss mice and introduced to Kunming, capital of Yunnan Province, China, from Indian Haffkine Institute in 1964, which have become one of the most important strains of mice widely used in medical research (27,28). Six-week-old female Kunming mice (provided by the Institute of Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China) were randomized into two groups (n = 3) and were given W peptide (0.43 mg/kg, 100 Amol/L W peptide, 100 AL) or PBS by i.p.…”

Section: Methodsmentioning

confidence: 99%

Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity

Lin¹,

Wei²,

Zhang³

et al. 2007

Molecular Cancer Therapeutics

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Formyl peptide receptor-like 1 (FPRL1), which is a G protein -coupled receptor of chemoattractant subfamily, plays an important role in the regulation of host defense against pathogenic infection and the chemotactic and activating effects of AB 42 on mononuclear phagocytes as well as in the elimination of damaged or pathogen-infected cells. In the present study, we showed that stimulation of FPRL1 agonist ligands (W peptide from a synthetic peptide library, N36 peptide from HIV-1 gp41, and F peptide from HIV-1 envelope protein gp120) elevated endogenous tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) expression in human THP-1 monocytes, primary neutrophils, and mouse leukocytes. Activation of nuclear factor KB was required by the FPRL1-mediated TRAIL expression in the human THP-1 cells and primary neutrophils. The increased TRAIL expression in the mice significantly suppressed the growth of transplanted mouse liver tumor cells by inducing apoptotic cell death. Together, these data provide novel evidence for the physiologic role of FPRL1 and TRAIL in tumor immune surveillance and innate immunity, and implicate a novel strategy for cancer therapy by triggering the endogenous TRAIL expression via stimulation of G protein -coupled receptor FPRL1. [Mol Cancer Ther 2007;6(10):2618 -25]

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R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II

Cited by 77 publications

References 40 publications

G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation

G226, a new epipolythiodioxopiperazine derivative, triggers DNA damage and apoptosis in human cancer cells in vitro via ROS generation

B1, a Novel Amonafide Analogue, Overcomes the Resistance Conferred by Bcl-2 in Human Promyelocytic Leukemia HL60 Cells

Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity

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