AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C

Vučićević, Ljubica; Misirkić, Maja; Janjetović, Kristina; Harhaji-Trajković, Ljubica; Prica, Marko; Stevanović, Darko; Isenović, Esma R.; Sudar-Milovanović, Emina; Šumarac-Dumanović, Mirjana; Micić, Dragan; Trajkovič, Vladimir

doi:10.1016/j.bcp.2009.03.005

Cited by 56 publications

(72 citation statements)

References 30 publications

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“…The inhibition of AMPK leads to cell death (69) and the suppression of proliferation (74) in some cell types, but we did not observe any change in cell numbers during our experiments, indicating that the reduction in the release of inflammatory mediators was not the result of decreased cell numbers. Similar to our observations that AMPK agonists ( Figure 6) suppressed as well as AMPK inhibitors suppressed the release of cytokine from HASM cells (Figure 7), others showed that the proliferation of other cell types is blocked by AICAR (75) or by other conditions that lead to the activation of AMPK, such as glucose depletion (76), and also by the AMPK inhibitor Compound C (69,77). The data suggest an energy optimum that, if disturbed in either direction, impairs cell function.…”

Section: Discussionsupporting

confidence: 90%

“…To examine the role of TZD-induced AMPK activation further, we used two chemically dissimilar inhibitors to block the AMPK pathway, Compound C (59) and Ara A (60), at doses reported by others to inhibit the activation of AMPK (68)(69)(70)(71). Both antagonists prevented the AICAR-induced activation of AMPK, as assessed by the Thr 172 phosphorylation of AMPK ( Figure 7A), indicating that they were active at the concentrations administered.…”

Section: Discussionmentioning

confidence: 90%

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Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Zhu¹,

Flynt

Ghosh

et al. 2011

Am J Respir Cell Mol Biol

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Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dosedependently reduced the IL-1b-induced release of IL-6 and vascular endothelial growth factor, the TNF-a-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-a-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-g (PPARg), these anti-inflammatory effects were not affected by a specific PPARg inhibitor (GW 9662) or by the knockdown of PPARg using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the antiinflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARg or AMPK.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Zhu¹,

Flynt

Ghosh

et al. 2011

Am J Respir Cell Mol Biol

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“…As shown in Reactive oxygen species (ROS) may mediate down-regulation of c-FLIP L and Mcl-1 by compound C Numerous investigations have documented that oxidative stressmediated cellular changes are frequently induced following exposure to cytotoxic drugs, UV or γ-irradiation [17,18]. It has been reported that compound C increases ROS production in glioma cells [19]. Therefore, we examined whether ROS generation might be involved in compound C plus TRAIL-induced apoptosis.…”

Section: Compound C Decreases the Expressions Of C-flip L And Mcl-1 Bmentioning

confidence: 96%

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

Lee

Yang

et al. 2010

Experimental Cell Research

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“…59 Compound C (pyrrazolopyrinidine derivate) is a selective ATP-competitive inhibitor of AMPK that induced apoptosis in myeloma cell lines in the absence of any stress. 60 We therefore evaluated the effect of AMPK inhibition on the human glioma cell line (U251) using compound C. 61 Compound C decreased both the cell number and mitochondrial dehydrogenase activity in a dose-dependent manner. There was a considerable change in morphology of treated cells, suggesting cell death.…”

Section: Gliomasmentioning

confidence: 99%

Metformin: Its emerging role in oncology

Micić¹,

Cvijović²,

Trajkovič³

et al. 2011

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Metformin is considered, in conjunction with lifestyle modification, as a first-line treatment modality for type 2 diabetes mellitus (DM). recently, several clinical studies have reported reduced incidence of neoplastic diseases in DM type 2 patients treated with metformin, as compared to diet or other antidiabetic agents. Moreover, in vitro studies have disclosed significant antiproliferative and proapoptotic effects of metformin on different types of cancer. Metformin acts by activating AMP-activated protein kinase (AMPK), a key player in the regulation of energy homeostasis. Moreover, by activating AMPK, metformin inhibits the mammalian target of rapamycin complex 1 (mtOrc1) resulting in decreased cancer cell proliferation. concomitantly, metformin induces activation of LKb1 (serine/threonine kinase 11), a tumor suppressor gene, which is required for the phosphorylation and activation of AMPK. these new encouraging experimental data supporting the anti-cancer effects of metformin urgently require further clinical studies in order to establish its use as a synergistic therapy targeting the AMPK/mtOr signaling pathway.

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AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C

Cited by 56 publications

References 30 publications

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

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

Metformin: Its emerging role in oncology

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