Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase

Lemke, Leslie E.; Paine-Murrieta, Gillian; Taylor, Charles W.; Powis, Garth

doi:10.1007/s002800051123

Cited by 35 publications

(25 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to this, Schultz et al [25] demonstrated inhibition of PI3K activity by wortmannin to inhibit growth of the murine C3H mammary carcinoma and the human BxPC3 pancreatic tumor in a xenograft model. These findings were reproduced by Lemke et al [17] in murine MCF-7 and C3H mammary tumors. However, according to Schultz et al [25], the ability of wortmannin to inhibit C3H tumor growth is not related to inhibition of tumor PI3K activity, suggesting an additional site of action for wortmannin to inhibit tumor growth.…”

Section: Discussionsupporting

confidence: 83%

“…PI3K has been identified as a potential target for anticancer drug development because of its role as a component of growth factor and oncogene activated signaling pathways [14]. Wortmannin (C 23 H 24 0 8 ), a highly cell permeable fungal metabolite from Penicillium fumiculosum, acts as a selective, irreversible inhibitor of the catalytic p110 PI3K subunit [15,16,17,18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo

Boehle

Kurdow

Boenicke

et al. 2002

Langenbeck's Archives of Surgery

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo

Boehle

Kurdow

Boenicke

et al. 2002

Langenbeck's Archives of Surgery

View full text Add to dashboard Cite

show abstract

“…PI 3-K inhibitors such as wortmannin and LY294002 are known to possess anti-tumor activities (30,31) and previous studies have indicated that the PI 3-K/Akt signaling pathway can modulate TRAIL-mediated apoptosis in cancer cells (22)(23)(24)32,33). Therefore, we used HSC-2 and NA cell lines, which are resistant to TRAIL-induced apoptosis, to examine the effect of treatment with PI 3-K inhibitors on susceptibility to apoptosis via this process.…”

Section: Discussionmentioning

confidence: 99%

Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors

Uchida

Iwase²,

Takaoka³

et al. 2007

Int J Oncol

View full text Add to dashboard Cite

Abstract. In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAILmediated apoptosis in OSCC cells.

show abstract

“…38 Several studies have reported that wortmannin has an antitumor effect in human breast cancer cell lines, and are inconsequential in the MCF-7 context, specifically from the programmed cell death perspective. [39][40][41][42][43] To the best of our knowledge, there are no further reports on the details of the mechanism of action on MCF-7 cell death. Therefore, we have explored for the first time the possible mechanism of cell death induced by wortmannin in MCF-7 cells by focusing on its ability to induce programmed cell death.…”

Section: Discussionmentioning

confidence: 99%

Wortmannin induces MCF-7 breast cancer cell death via the apoptotic pathway, involving chromatin condensation, generation of reactive oxygen species, and membrane blebbing

Akter¹,

Hossain²,

Kleve³

et al. 2012

BCTT

View full text Add to dashboard Cite

Background: Apoptosis can be used as a reliable marker for evaluating potential chemotherapeutic agents. Because wortmannin is a microbial steroidal metabolite, it specifically inhibits the phosphatidyl inositol 3-kinase pathway, and could be used as a promising apoptosis-based therapeutic agent in the treatment of cancer. The objective of this study was to investigate the biomolecular mechanisms involved in wortmannin-induced cell death of breast cancer-derived MCF-7 cells. Methods and results: Our experimental results demonstrate that wortmannin has strong apoptotic effects through a combination of different actions, including reduction of cell viability in a dose-dependent manner, inhibition of proliferation, and enhanced generation of intracellular reactive oxygen species. Conclusion: Our findings suggest that wortmannin induces MCF-7 cell death via a programmed pathway showing chromatin condensation, nuclear fragmentation, reactive oxygen species, and membrane blebbing, which are characteristics typical of apoptosis.

show abstract

Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase

Cited by 35 publications

References 15 publications

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo

Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors

Wortmannin induces MCF-7 breast cancer cell death via the apoptotic pathway, involving chromatin condensation, generation of reactive oxygen species, and membrane blebbing

Contact Info

Product

Resources

About