Potentiation of arsenic trioxide-induced apoptosis by 8-bromo-7-methoxychrysin in human leukemia cells involves depletion of intracellular reduced glutathione

Xiao, Guang-Fen; Tang, Xia; Yao, Chenjiao; Wang, Chenghong

doi:10.1093/abbs/gmr065

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…GSH depletion and H 2 O 2 accumulation with ATO treatment in H841 cells detected in this study are in keeping with previous reports (11,(49)(50)(51)(52). Nonetheless, the type and amount of ROS needed to initiate cell death by ATO are still controversial, which can vary with different cell lines and dose of ATO (53).…”

Section: Discussionsupporting

confidence: 91%

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

Zheng

Lam

et al. 2015

Int J Oncol

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Abstract. Arsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC 50 values below 10 µM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation. IntroductionSCLC, accounting for 15-20% of newly diagnosed lung cancer, is an extremely aggressive malignancy with early metastasis and poor prognosis. Despite a prompt response to chemotherapy, relapses occur in the majority of patients with SCLC. Therefore the development of an alternative therapy against SCLC becomes imperative (1).ATO has been proven to be an effective therapeutic agent in acute promyelocytic leukemia (APL) with high complete remission rate and prolonged survival (2,3). ATO can induce apoptosis through PML-RARα-independent pathways in APL or other cancer cells via p53 activation (4,5), Bcl-2 downregulation (6,7), mitochondrial membrane depolarization and cytochrome c release (8-10), depletion of intracellular reduced glutathione (GSH) content and elevation of reactive oxygen species (11,12). More recently, the application of ATO in lung cancer treatment has been explored in preclinical models, mainly in non-small cell lung cancer (NSCLC). ATO induces growth inhibition and apoptosis in NSCLC cells through G2/M cell cycle arrest (13,14), Bcl-2 downregulation and GSH depletion (15). Recently, downregulation of thymidylate synthase and E2F1 were obser...

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Section: Discussionsupporting

confidence: 91%

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

Zheng

Lam

et al. 2015

Int J Oncol

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“…8-bromo-7-methoxychrysin (BrMC) was synthesized previously based of the lead compound ChR (28). In addition, BrMC has strong effects of inhibition of proliferation and induction of apoptosis on various types of cancer (39,40). In the current study, we demonstrated that BrMC significantly reduced the activation of LX-2 induced by LCSLC-CM, and inhibited the properties of LCSLCs induced by LCAHSC-CM ( Fig.…”

Section: Discussionmentioning

confidence: 58%

Reversal of liver cancer-associated stellate cell-induced stem-like characteristics in SMMC-7721 cells by 8-bromo-7-methoxychrysin via inhibiting STAT3 activation

et al. 2016

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Hepatic stellate cells (HSCs) that are activated by human hepatocellular carcinoma (HCC) cells secrete a variety of cytokines, which are the main component of the HCC microenvironment. We aimed to determine whether 8-bromo-7-methoxychrysin (BrMC) could interfere in cross-talk of the human hepatic stellate cell line LX-2 and liver cancer stem-like cells (LCSLCs) to inhibit the characteristics of LCSLCs endowed with the capacity of sustaining human hepatocellular carcinoma (HCC) self-renewal and progression, and to identify its potential mechanism of action. We found that the levels of fibroblast activation protein (FAP) were augmented in LX-2 cells treated with the conditioned medium of LCSLCs (LCSLC-CM) compared to those cultured with routine medium, indicating that the LCSLC-CM can activate LX-2 cells to become liver cancer-associated stellate cells (LCAHSCs). Furthermore, sphere forming capability of SMMC-7721 cells was enhanced and stem cell-related protein expression was significantly increased following treatment with the conditioned medium of LCAHSCs (LCAHSC-CM). Moreover, the level of p-STAT3 was increased in LX-2 cells treated with LCSLC-CM and BrMC reduced expression of p-STAT3. Combination of BrMC and the selective inhibitor of STAT3 cucurbitacin I (JSI-124) synergistically suppressed the LCSLC characteristics in SMMC-7721 cells. Collectively, our data showed that BrMC inhibited the interaction between LX-2 cells and HCC-derived CSCs, and did so potentially through modulation of the STAT3 pathway. Future therapeutic strategies employing anti-CSC therapy should confirm the potential of cucurbitacin I (JSI-124) and BrMC as potent therapeutic agents.

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“…8-bromo-7-methoxychrysin (BrMC) a novel ChR derivative, has been reported to have anti-cancer activities with more potent bioactivity than the lead compound ( 11 – 14 ). It has been proposed that BrMC-induced cell cycle arrest and apoptosis may be the mechanisms of its anticancer effects ( 15 , 16 ). However, the precise underlying molecular mechanisms by which BrMC induces apoptosis in ovarian cancer cells are not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

8-bromo-7-methoxychrysin induces apoptosis by regulating Akt/FOXO3a pathway in cisplatin-sensitive and resistant ovarian cancer cells

Ding

Chen

Zhang

et al. 2015

Molecular Medicine Reports

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8-bromo-7-methoxychrysin (BrMC), a novel chrysin analog, was reported to have anti-cancer activities. The aim of the present study was to investigate the molecular mechanism of 8-bromo-7-methoxychrysin (BrMC)-induced apoptosis via the Akt/forkhead box O3a (FOXO3a) pathway in cisplatin (DDP)-sensitive and -resistant ovarian cancer cells. The human ovarian cancer cell lines A2780 and A2780/DDP were cultured in vitro. Various molecular techniques were used to assess the expression of FOXO3a and B cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim) in cisplatin-sensitive and -resistant ovarian cancer cells. Different concentrations of BrMC induced apoptosis in cisplatin-sensitive and -resistant ovarian cancer cells. BrMC-induced apoptotic cell death occurred mainly by the activation of Akt, which was accompanied by the overexpression of transcription factor FOXO3a, with a concomitant increase in the expression levels of Bim. Silencing Bim expression by using small interfering RNA, attenuated the induction of apoptosis by BrMC treatment. The results indicated that BrMC-induced apoptosis in cisplatin-sensitive and -resistant ovarian cancer cells may occur via the regulation of Akt/FOXO3a, leading to Bim transcription.

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Potentiation of arsenic trioxide-induced apoptosis by 8-bromo-7-methoxychrysin in human leukemia cells involves depletion of intracellular reduced glutathione

Cited by 5 publications

References 36 publications

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity

Reversal of liver cancer-associated stellate cell-induced stem-like characteristics in SMMC-7721 cells by 8-bromo-7-methoxychrysin via inhibiting STAT3 activation

8-bromo-7-methoxychrysin induces apoptosis by regulating Akt/FOXO3a pathway in cisplatin-sensitive and resistant ovarian cancer cells

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