Effects of Deguelin on the Phosphatidylinositol 3-Kinase/Akt Pathway and Apoptosis in Premalignant Human Bronchial Epithelial Cells

Chun, Kyung–Hee; Kosmeder, Jerome W.; Sun, Shihua; Pezzuto, John M.; Lotan, Reuben; Hong, Waun Ki; Lee, Ho‐Young

doi:10.1093/jnci/95.4.291

Cited by 246 publications

(236 citation statements)

References 38 publications

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“…7 In addition, deguelin was suggested to be useful for chemoprevention and the induction of apoptosis in lung carcinogenesis and for therapy in confirmed lung cancer. [8][9][10][11][12] It was shown that the pro-apoptotic activity of deguelin in premalignant and malignant bronchial epithelial cells was caused by the inhibition of phosphoinositide-3 kinase (PI3K) activity and the reduction of Akt phosphorylation. 12 Furthermore, Bortul et al 13 described that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukemic cells with an active PI3K/Akt signaling network.…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10][11][12] It was shown that the pro-apoptotic activity of deguelin in premalignant and malignant bronchial epithelial cells was caused by the inhibition of phosphoinositide-3 kinase (PI3K) activity and the reduction of Akt phosphorylation. 12 Furthermore, Bortul et al 13 described that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukemic cells with an active PI3K/Akt signaling network. Because activated Akt can affect numerous cellular functions via intermediary molecules, including mTOR, NF-kB and p53, which control cell survival, growth and proliferation, effective inhibition of PI3K/Akt by deguelin means it can affect the activation of NF-kB.…”

Section: Introductionmentioning

confidence: 99%

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Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

et al. 2007

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We investigated if deguelin, a naturally occurring rotenoid, was able to inhibit nuclear factor kappa B (NF-jB)-binding protein (IjBa) expression and to induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro. Deguelin-induced cell death in the majority of B-CLL cells and was found to be more toxic toward B-CLL cells than to the normal mononuclear or B-cells, suggesting selectivity towards the malignant cells. Deguelin was found to reduce IjBa protein expression, and thus interacts with the NFjB pathway. The induced apoptosis was characterized by processing of caspase-9 and -3 and poly-(ADP)-ribose-polymerase cleavage. Exposure of B-CLL cells to deguelin resulted in Bcl2-associated protein (Bax) conformational changes and downregulation of the key survival protein myeloid cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. Deguelin retained its ability to induce apoptosis in B-CLL cells in the presence of interleukin-4, a pro-survival cytokine in B-CLL, and when cultured with 50% human serum. These data indicate that deguelin is able to induce apoptosis in B-CLL cells in the presence of pro-survival signals and thus merits further investigation for clinical application either as a single agent or in combination with other anticancer agents.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

et al. 2007

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“…Clear evidence shows that the PI3K/Akt signalling pathway is involved in lung carcinogenesis (Brognard et al, 2001;Chun et al, 2003;Lee et al, 2003;Tsao et al, 2003;Massion et al, 2004). Akt is frequently activated in both premalignant human bronchial epithelial cells and NSCLC cells.…”

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confidence: 99%

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

et al. 2008

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c-Jun is a major constituent of AP-1 transcription factor that transduces multiple mitogen growth signals, and it is frequently overexpressed in non-small cell lung cancers (NSCLCs). Earlier, we showed that blocking AP-1 by the overexpression of a c-Jun dominant-negative mutant, TAM67, inhibited NSCLC cell growth. The phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway is important in transformation, proliferation, survival and metastasis of NSCLC cells. In this study, we used NCI-H1299 Tet-on clone cells that express TAM67 under the control of inducible promoter to determine the effects of inhibition of AP-1 and PI3K on cell growth. The PI3K inhibitor, LY294002, produced a dose-dependent inhibition of growth in H1299 cells and that inhibition was enhanced by TAM67. TAM67 increased dephosphorylation of Akt induced by LY294002 and reduced the TPA response element DNA-binding of phosphorylated c-Jun. TAM67 increased G1 cell cycle blockade induced by LY294002, which was partially associated with cyclin A decrease and p27 Kip1 accumulation. Furthermore, TAM67 and LY294002 act, at least additively, to inhibit anchorage-independent growth of the H1299 cells. These results suggest that AP-1 and PI3K/Akt pathways play an essential role in the growth of some NSCLC cells.

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“…This finding was confirmed by caspase activity assay. Many well-known phytochemicals that can safely modulate physiological function and enhance anti-cancer activity induce apoptosis through mitochondrial pathway (Chun et al, 2003;Gupta et al, 2013). Similarly, FEOJ induced apoptosis through induction of loss of MMP (ΔΨm).…”

Section: Discussionmentioning

confidence: 99%

Flavonoids from Orostachys Japonicus A. Berger Induces Caspase-dependent Apoptosis at Least Partly through Activation of p38 MAPK Pathway in U937 Human Leukemic Cells

Lee¹,

Yun²,

Nagappan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Effects of Deguelin on the Phosphatidylinositol 3-Kinase/Akt Pathway and Apoptosis in Premalignant Human Bronchial Epithelial Cells

Cited by 246 publications

References 38 publications

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

Flavonoids from Orostachys Japonicus A. Berger Induces Caspase-dependent Apoptosis at Least Partly through Activation of p38 MAPK Pathway in U937 Human Leukemic Cells

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