E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

Ogino, Hirokazu; Hashimoto, Masaki; Kakiuchi, Soji; Goto, Hisatsugu; Ikuta, Kenji; Yamada, Tadaaki; Uehara, Hisanori; Tsuruoka, Akihiko; Uenaka, Toshimitsu; Wang, Wei; Li, Qi; Takeuchi, Shinji; Yano, Seiji; Nishioka, Yasuhiko; Sone, Saburo

doi:10.1158/1535-7163.mct-10-0707

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…Note that these cells were not pretreated with EGF or any other NFκB activator. A549, OVCAR3, H1048, and SW1271 cells have wild-type EGFR (27)(28)(29)(30), whereas HCC827 cells carry an activating EGFR mutation (31). As expected, erlotinib inhibits EGFR phosphorylation in all of these cells and, importantly, it also decreases greatly the phosphorylation of IκB, within 2-3 h (Fig.…”

Section: Egfr Mediates Nfκb Activation In Several Cancer Cell Linessupporting

confidence: 70%

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dermawan

Stark

2014

Proc. Natl. Acad. Sci. U.S.A.

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Activation of nuclear factor κB (NFκB) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NFκB. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response. Down-regulating EGFR expression or inhibiting EGFR with erlotinib impairs constitutive NFκB activation in several different types of cancer cells and, conversely, increased activation of NFκB leads to erlotinib resistance in these cells. We conclude that EGF is an important mediator of NFκB activation in cancer cells. To explore the mechanism, we selected an erlotinibresistant cell line in which the guanine nucleotide exchange factor Son of Sevenless 1 (SOS1), well known to be important for EGFdependent signaling to MAP kinases, is overexpressed. Increased expression of SOS1 increases NFκB activation in several different types of cancer cells, and ablation of SOS1 inhibits EGF-induced NFκB activation in these cells, indicating that SOS1 is a functional component of the pathway connecting EGFR to NFκB activation. Importantly, the guanine nucleotide exchange activity of SOS1 is not required for NFκB activation.

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Section: Egfr Mediates Nfκb Activation In Several Cancer Cell Linessupporting

confidence: 70%

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dermawan

Stark

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In this model, SBC-3 and H1048 cells expressing high levels of Dll4 metastasized to the liver, kidney, bone, and lymph node (17,18). We observed that SBC-3-Dll4-Fc and H1048-Dll4-Fc cells produced significantly fewer numbers of metastatic nodules in the liver compared with the control cells ( Table 1).…”

Section: Dll4-fc Suppresses Liver Metastasis Of Sclc Cells Expressingmentioning

confidence: 73%

“…Two days later, the mice were inoculated with SBC-3, H1048, or SBC-5 cells into the tail vein (16)(17)(18). The mice were sacrificed humanely under anesthesia, and the major organs were then removed and weighed and the number of metastatic nodules on the surface of the organs was counted.…”

Section: In Vivo Metastasis Modelsmentioning

confidence: 99%

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Kuramoto

Goto

Mitsuhashi

et al. 2012

Molecular Cancer Therapeutics

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Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-kB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-kB activities, both with and without stimulation by TNF-a, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-kB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-kB signaling.

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“…VEGF plays an important role in tumor growth and is involved in angiogenesis, in relation to the development of metastasis. Lenvatinib showed potent antitumor efficacy with a broad spectrum of human tumor xenograft models, on the basis of inhibitory activity toward VEGF receptors 2 and 3 (Matsui et al, 2008a;Ikuta et al, 2009;Ogino et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Unique Metabolic Pathway of [¹⁴C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey

Inoue¹,

Asai²,

Mizuo³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Lenvatinib, a potent inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 2 and 3, generated unique metabolites after oral administration of [ 14 C]lenvatinib (30 mg/kg) to a male cynomolgus monkey. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by ␥-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Characteristic product ions at m/z 235 and m/z 244, which were associated with thioquinoline and N-ethylquinoline derivatives, respectively, were used to differentiate S-and N-derivatives in this study. On the basis of accurate mass and NMR measurements, a unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated.

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E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

Cited by 16 publications

References 38 publications

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Unique Metabolic Pathway of [¹⁴C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey

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E7080 Suppresses Hematogenous Multiple Organ Metastases of Lung Cancer Cells with Nonmutated Epidermal Growth Factor Receptor

Cited by 16 publications

References 38 publications

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

Dll4-Fc, an Inhibitor of Dll4-Notch Signaling, Suppresses Liver Metastasis of Small Cell Lung Cancer Cells through the Downregulation of the NF-κB Activity

Unique Metabolic Pathway of [14C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey

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Unique Metabolic Pathway of [¹⁴C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey