Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest

Dan, Shingo; Haga, Yoshimi; Okamura, Mutsumi; Mukai, Yumiko; Yamori, Takao

doi:10.1016/j.bbrc.2008.12.015

Cited by 44 publications

(43 citation statements)

References 20 publications

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“…PI3K inhibitors have been found to induce G0/G1 cell arrest rather than apoptosis, and primarily causing stasis of tumor growth in vivo without substantial tumor shrinkage. For example, intraperitoneal administration of high doses of PI-103 (30-70 mg/kg) resulted in growth inhibition rather than regression in a range of human tumor xenografts (12,30). Moreover, in EGFR mutant or k-ras mutant lung cancer models, tumor regression associating with apoptosis was observed only when PI3K/Akt pathway and MEK/MAPK pathway were simultaneously blocked (24,31).…”

Section: Discussionmentioning

confidence: 99%

Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs inEGFRMutant Lung Cancer

Donev

Wang

Yamada

et al. 2011

Clinical Cancer Research

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Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET that restores downstream mitogen activated protein kinase (MAPK)/ extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells PC-9 and HCC827.Experimental Design: We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo.Results: Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model by using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments by considering short half-life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF.Conclusions: These results indicate that transient blockade of PI3K/Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in EGFR mutant lung cancer.

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Section: Discussionmentioning

confidence: 99%

Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs inEGFRMutant Lung Cancer

Donev

Wang

Yamada

et al. 2011

Clinical Cancer Research

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“…The protein p27 KIP1 , an inhibitor of cyclin-dependent kinase-2, was induced by ZSTK474 and may be responsible to the arrest of cells in G 1 -phase. 25 Increases in phospho-Akt in some cells are due to an inhibitory feedback mechanism between the mTOR effector p70S6K and the insulin receptor substrate-PI3K upstream of Akt. 26 Our previous results are consistent with reports that inhibition of mTOR signaling by rapamycin increases Akt phosphorylation in MCF-7 cells.…”

Section: Methodsmentioning

confidence: 99%

Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells

Leung

Kim

Rewcastle

et al. 2011

Cancer Biology & Therapy

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“…In vitro, ZSTK474 inhibited the growth of 39 human cancer [11] , ( Figure 4A) and blocked cell cycle progression at G 0 /G 1 phase in various human cancer cells without obvious induction of apoptosis [11,66] . The G 0 /G 1 arrest effect might be attributed to inactivation of cyclin D1, enhanced expression of p27, and the following pRB dephosphorylation [66] .…”

Section: Pi3k a Promising Molecular Target For Cancer Chemo Therapymentioning

confidence: 98%

“…The G 0 /G 1 arrest effect might be attributed to inactivation of cyclin D1, enhanced expression of p27, and the following pRB dephosphorylation [66] . Moreover, ZSTK474 showed potent anti-angiogenic effect [67] .…”

Section: Pi3k a Promising Molecular Target For Cancer Chemo Therapymentioning

confidence: 99%

“…The in vivo anti-angiogenic effect is attributed to its dual inhibition mechanism: inhibition of VEGF secretion by cancer cells and direct inhibition of PI3K in endothelial cells [67] . Oral administration of ZSTK474 indicated favorable in vivo antitumor efficacy on various cancer xenografts at both early and advanced stages, without any obvious toxicity [66][67][68] ( Figure 4C). The expression of phospho-Akt (ser 473) correlates with antitumor efficacy, suggesting this could act as a predictive biomarker [68] .…”

Section: Pi3k a Promising Molecular Target For Cancer Chemo Therapymentioning

confidence: 99%

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ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

Kong

Yamori

2010

Acta Pharmacol Sin

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JFCR39 is an informatic anticancer drug discovery system that utilizes a panel of 39 human cancer cells coupled with a drug-activity database. This system not only provides disease-oriented information but can also predict the mechanism of action of a given antitumor agent. Development of a phosphatidylinositol 3-kinase (PI3K) inhibitor as an anticancer drug candidate has attracted a great deal of attention from both academia and industry because PI3K is known to be closely involved in carcinogenesis. ZSTK474 was identified as a PI3K inhibitor using JFCR39 system in combination with COMPARE analysis program. These findings were based on the similar fingerprint (growth inhibition profiles for JFCR39 human cancer cell line panel) with that of a classical PI3K inhibitor LY294002. Biochemical experiments confirmed ZSTK474 to be a potent pan-class I PI3K inhibitor, with high selectivity over other classes of PI3K and protein kinases. We previously reported the in vitro and in vivo antitumor efficacy of ZSTK474, together with the G 0 /G 1 arrest and antiangiogenic activity. Here, we review the JFCR39 system and summarize recent studies on PI3K biology and the development of PI3K inhibitors before discussing ZSTK474 in some detail.

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Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest

Cited by 44 publications

References 20 publications

Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs inEGFRMutant Lung Cancer

Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs inEGFRMutant Lung Cancer

Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

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