The Use of Tyrosine Kinase Inhibitors in Modifying the Response of Tumor Microvasculature to Radiotherapy

Lü, Bo; Shinohara, Eric T.; Edwards, E.; Geng, Li; Tan, Jason; Hallahan, Dennis E.

doi:10.1177/153303460500400614

Cited by 15 publications

(11 citation statements)

References 49 publications

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“…HPIs have been shown to attenuate angiogenesis in numerous tumor models. Previous reports have shown that attenuating the PI3K/Akt pathway enhances the antiangiogenic effect of ionizing radiation (15,22,30,36,37). In the current study, we examined the effect of HPIs and radiation on endothelial cell function.…”

Section: Discussionmentioning

confidence: 96%

“…Furthermore, a recent report suggests that HPIs have the ability to sensitize tumor cells with constitutively active PI3K signaling to the cytotoxic effects of ionizing radiation (12). We and others have previously shown that the PI3K/Akt pathway is activated in HUVECs after ionizing radiation (18,22,30,32,33) and compounds that inhibit this pathway sensitize endothelial cells to radiation. In the current study, nelfinavir was found to attenuate the phosphorylation of Akt as well as Erk to a lesser extent after 3 Gy, a clinically relevant dose.…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, the inhibition of VEGF receptor signaling affects radiation-induced destruction of tumor vasculature by blocking PI3K/Akt signaling (20)(21)(22). Most recently, nelfinavir has been shown to down-regulate VEGF expression in tumor cells via hypoxia-inducible factor 1a to contribute to radiation sensitivity (23).…”

Section: Introductionmentioning

confidence: 99%

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HIV Protease Inhibitors Enhance the Efficacy of Irradiation

Cuneo

Geng

et al. 2007

Cancer Research

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Tumor vascular endothelium is rather resistant to the cytotoxic effects of radiation. The HIV protease inhibitors (HPI) amprenavir, nelfinavir, and saquinavir have previously been shown to sensitize tumor cells to the cytotoxic effects of radiation. Additionally, this class of drug has been shown to inhibit angiogenesis and tumor cell migration. Therefore, in the current study, we wanted to determine whether HPIs could enhance the effect of radiation on endothelial function. Our study shows that HPIs, particularly nelfinavir, significantly enhance radiation's effect on human umbilical vein endothelial cells (HUVEC) and tumor vascular endothelium. We show that pretreatment of HUVEC with nelfinavir results in enhanced cytotoxicity, including increased apoptosis, when combined with radiation. Moreover, using several functional assays, we show that combination treatment effectively blocks endothelial cell migration and organization. These findings were accompanied by attenuation of Akt phosphorylation, a known pathway for radioresistance. Last, in vivo analysis of tumor microvasculature destruction showed a more than additive effect for nelfinavir and radiation. This study shows that HPIs can enhance the effect of ionizing radiation on vascular endothelium. Therefore, the Food and Drug Administrationapproved drug, nelfinavir, may be an effective radiosensitizer in the clinic. [Cancer Res 2007;67(10):4886-93]

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

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HIV Protease Inhibitors Enhance the Efficacy of Irradiation

Cuneo

Geng

et al. 2007

Cancer Research

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“…We and others have shown that radiation induces Akt phosphorylation (4,29,(34)(35)(36). A, endothelial cell closure assay is shown in which 80% confluent HUVEC were subjected to a gap formation using a 200 AL pipette tip.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow X Kinase–Mediated Signal Transduction in Irradiated Vascular Endothelium

Thotala

Geng

et al. 2008

Cancer Research

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“…Many proangiogenic growth factors regulate angiogenesis through PI3K/Akt and MKK/ ERK signaling pathways (Kim et al, 2004;Lu et al, 2005;Perona, 2006). MKK/ERK signaling pathway has been shown to play a crucial role in tumori- genesis and tumor metastasis (Ward et al, 2001;Huang et al, 2008), and sustained activation of ERK has been established as a requirement for angiogenesis (Berra et al, 2000;Dong et al, 2001;Depeille et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

5-Formylhonokiol exerts anti-angiogenesis activityviainactivating the ERK signaling pathway

Zhu

et al. 2011

Exp Mol Med

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Abbreviations: FH, 5-formylhonokiol; HK, honokiol; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B AbstractOur previous report has demonstrated that 5-formylhonokiol (FH), a derivative of honokiol (HK), exerts more potent anti-proliferative activities than honokiol in several tumor cell lines. In present study, we first explored the antiangiogenic activities of 5-formylhonokiol on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) for the first time in vitro. Then we investigated the in vivo antiangiogenic effect of 5-formylhonokiol on zebrafish angiogenesis model. In order to clarify the underlying molecular mechanism of 5-formylhonokiol, we investigated the signaling pathway involved in controlling the angiogenesis process by western blotting assay. Wound-healing results showed that 5-formylhonokiol significantly and dose-dependently inhibited migration of cultured human umbilical vein enthothelial cells. The invasiveness of HUVEC cells was also effectively suppressed at a low concentration of 5-formylhonokiol in the transwell assay. Further F-actin imaging revealed that inhibitory effect of 5-formylhonokiol on invasion may partly contribute to the disruption of assembling stress fiber. Tube formation assay, which is associated with endothelial cells migration, further confirmed the anti-angiogenesis effect of 5-formylhonokiol. In in vivo zebrafish angiogenesis model, we found that 5-formylhonokiol dose-dependently inhibited angiogenesis. Furthermore, western blotting showed that 5-formylhonokiol significantly down-regulated extracellular signal-regulated kinase (ERK) expression and inhibited the phosphorylation of ERK but not affecting the total protein kinase B (Akt) expression and related phosphorylation, suggesting that 5-formylhonokiol might exert anti-angiogenesis capacity via down-regulation of the ERK signal pathway. Taken together, these data suggested that 5-formylhonokiol might be a viable drug candidate in antiangiogenesis and anticancer therapies.

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The Use of Tyrosine Kinase Inhibitors in Modifying the Response of Tumor Microvasculature to Radiotherapy

Abstract: The response of the tumor microvasculature to ionizing radiation can be modified to improve tumor control in preclinical mouse models of cancer. Recent studies have shown that a variety of cancer drugs can improve the response of cancers to radiotherapy.

Cited by 15 publications

References 49 publications

HIV Protease Inhibitors Enhance the Efficacy of Irradiation

HIV Protease Inhibitors Enhance the Efficacy of Irradiation

Bone Marrow X Kinase–Mediated Signal Transduction in Irradiated Vascular Endothelium

5-Formylhonokiol exerts anti-angiogenesis activityviainactivating the ERK signaling pathway

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