Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1

Jang, Ji Hoon; Lee, Tae Jin; Yang, Eun Sun; Min, Do Sik; Kim, Young Ho; Kim, Sang Hyun; Choi, Yung Hyun; Park, Jong Wook; Choi, Kyeong Sook; Kwon, Taeg Kyu

doi:10.1016/j.yexcr.2010.04.028

Cited by 38 publications

(32 citation statements)

References 33 publications

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“…The antiproliferative effect of compound C is concentration-dependent: a threshold effect of compound C on cell growth is observed at 0.2 M and is almost complete at 10 M. Of note, compound C inhibits cell proliferation in the absence of cell death, as revealed by trypan blue staining and propidium iodide binding, indicating that compound C functions as a cytostatic rather cytotoxic agent. The failure of these concentrations of compound C to evoke apoptosis is consistent with reports in astrocytes and melanoma cells but contrast with findings in glioma cells, renal cancer cells, and breast carcinoma cells in which similar concentrations of compound C stimulate apoptosis (Jin et al, 2009;Vucicevic et al, 2009;Jang et al, 2010). Thus, compound C appears to exert cytostatic effects in a cell-specific manner.…”

Section: Discussionsupporting

confidence: 86%

Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Peyton

Yan²,

Yates³

et al. 2011

J Pharmacol Exp Ther

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6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyrazolo [1,5-a] pyrimidine (compound C) is a cell-permeable pyrrazolopyrimidine derivative that acts as a potent inhibitor of AMPactivated protein kinase (AMPK). Although compound C is often used to determine the role of AMPK in various physiological processes, it also evokes AMPK-independent actions. In the present study, we investigated whether compound C influences vascular smooth muscle cell (SMC) function through the AMPK pathway. Treatment of rat aortic SMCs with compound C (0.02-10 M) inhibited vascular SMC proliferation and migration in a concentration-dependent fashion. These actions of compound C were not mimicked or affected by silencing AMPK␣ expression or infecting SMCs with an adenovirus expressing a dominant-negative mutant of AMPK. In contrast, the pharmacological activator of AMPK 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside inhibited the proliferation and migration of SMCs in a manner that was strictly dependent on AMPK activity. Flow cytometry experiments revealed that compound C arrested SMCs in the G 0 /G 1 phase of the cell cycle, and this was associated with a decrease in cyclin D1 and cyclin A protein expression and retinoblastoma protein phosphorylation and an increase in p21 protein expression. Finally, local perivascular delivery of compound C immediately after balloon injury of rat carotid arteries markedly attenuated neointima formation. These studies identify compound C as a novel AMPKindependent regulator of vascular SMC function that exerts inhibitory effects on SMC proliferation and migration and neointima formation after arterial injury. Compound C represents a potentially new therapeutic agent in treating and preventing occlusive vascular disease.

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Section: Discussionsupporting

confidence: 86%

Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Peyton

Yan²,

Yates³

et al. 2011

J Pharmacol Exp Ther

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“…9,11) Moreover, a previous report showed that compound C inhibition of fas-associated protein with death domain-like apoptosis regulator and myeloid cell leukemia-1 in renal cancer cells was mediated by ROS, which indicates that distinct actions of compound C might originate via ROS production. 12) Hepatic parenchymal cells including HepG2 produce ROS mostly from mitochondria. 31) Therefore, we examined whether compound C altered mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

“…9,10) Compound C has been shown to induce apoptosis in various cells. [11][12][13] It increases ceramide formation and affects the localization of Bax in breast cancer cells. 13) In addition, compound C induces cell cycle arrest in glioma cells and sensitizes tumor necrosis factor-related apoptosis-inducing ligand-dependent apoptosis in renal cancer cells.…”

mentioning

confidence: 99%

“…13) In addition, compound C induces cell cycle arrest in glioma cells and sensitizes tumor necrosis factor-related apoptosis-inducing ligand-dependent apoptosis in renal cancer cells. 11,12) In many reports, compound C-induced cell death has been found to be accompanied by oxidative stress. Compound C increases reactive oxygen species (ROS) production, which in turn stimulates apoptotic signaling cascades.…”

mentioning

confidence: 99%

“…Compound C increases reactive oxygen species (ROS) production, which in turn stimulates apoptotic signaling cascades. 11,12) Pretreatment with antioxidants can reverse compound C-mediated detrimental cellular events. 9,12) Because oxidative stress increases AMPK activity, it is uncertain that AMPK inhibition by compound C is required in those processes.…”

mentioning

confidence: 99%

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Compound C Increases Sestrin2 Expression <i>via</i> Mitochondria-Dependent ROS Production

Seo

et al. 2016

Biological & Pharmaceutical Bulletin

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Compound C is a widely used chemical inhibitor that down-regulates AMP-activated protein kinase (AMPK) activity. However, it has been suggested that compound C exerts AMPK-independent effects in various cells. Here, we investigated whether compound C induces Sestrin2 (SESN2), an antioxidant enzyme induced by diverse stress. In addition, the mechanism responsible for SESN2 induction by compound C was determined. Our results showed that compound C increased SESN2 protein expression in HepG2 cells in a concentration-and time-dependent manner. The induction of SESN2 mRNA was also observed in cells treated with compound C. Increase of SESN2 luciferase activity confirmed transcriptional regulation by compound C and this substance also increased nuclear factor erythroid 2 (NF-E2)-related factor-2 (Nrf2) phosphorylation, which implies that Nrf2 was involved in SESN2 induction. Next, we sought to demonstrate whether production of reactive oxygen species (ROS) accompanied SESN2 expression. Compound C increased ROS production, but this effect was prevented by pretreatment with antioxidants or the mitochondrial complex I inhibitor. Moreover, cyclosporin A, an inhibitor of pore formation in the mitochondrial membrane, attenuated compound C-induced SESN2 induction. However, overexpression of a constitutively active form of AMPK was not able to abolish SESN2 induction by compound C, which implies that its action is independent of AMPK inhibition. In conclusion, this is the first study demonstrating that compound C alters mitochondrial function and induces ROS production, which ultimately leads to phosphorylation of Nrf2 and induction of SESN2.

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BAI, A novel cyclin‐dependent kinase inhibitor induces apoptosis in A549 cells through activation of caspases and inactivation of Akt

Kim

Lee

Jang

et al. 2012

J of Cellular Biochemistry

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Previously, we have synthesized a novel cyclin-dependent kinase (CDK) inhibitor, 2-[1,1'biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ(6) -isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide (BAI) and reported its anti-cancer activity in head and neck cancer cells. In this study, we further evaluated the effect of BAI on growth of various human cancer cell lines, including A549 (nonsmall cell lung cancer), HCT116 (colon), and Caki (kidney). Profoundly, results of XTT and clonogenic assays demonstrated that BAI at nanomolar concentrations (20-60 nM) inhibited growth of A549, HCT116, and Caki cells, suggesting the anti-cancer potency. We show that BAI induced a dose-dependent apoptotic cell death in these human cancer cells, as measured by fluorescence-activated cell sorting (FACS). Interestingly, further biochemical analysis showed that treatment with BAI at 20 nM induced apoptosis in A549 cells in association with activation of caspases, cleavage of phospholipase C-γ1 (PLC-γ1), and inhibition of Akt in A549 cells. Importantly, pharmacological inhibition study revealed that pretreatment with z-VAD-fmk, a pan caspase inhibitor strongly blocked the BAI-induced apoptosis in A549 cells. Transfection analysis with Akt cDNA encoding constitutively active Akt further addressed the significance of Akt inhibition in the BAI-induced apoptosis in A549 cells. Notably, disruption of the PI3K/Akt pathway by LY294002, a PI3K/Akt inhibitor potentiated apoptosis in A549 cells by BAI at a subcytotoxic concentration. These findings collectively suggest that BAI potently inhibits growth of A549, HCT116, and Caki cells, and that the BAI-induced apoptosis in A549 cells is associated with activation of caspases, and inhibition of Akt.

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Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1

Cited by 38 publications

References 33 publications

Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Compound C Inhibits Vascular Smooth Muscle Cell Proliferation and Migration in an AMP-Activated Protein Kinase-Independent Fashion

Compound C Increases Sestrin2 Expression <i>via</i> Mitochondria-Dependent ROS Production

BAI, A novel cyclin‐dependent kinase inhibitor induces apoptosis in A549 cells through activation of caspases and inactivation of Akt

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