Endostatin therapy reveals a U-shaped curve for antitumor activity

Sjin, Robert M. Tjin Tham; Naspinski, Jennifer; Birsner, Amy E.; Li, C.; Chan, Roger W.; Lo, Kin-Ming; Gillies, Stephen D.; Zurakowski, David; Folkman, Judah; Samulski, Jude; Javaherian, Kashi

doi:10.1038/sj.cgt.7700938

Cited by 49 publications

(35 citation statements)

References 43 publications

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“…It appears that sEH inhibition or EETs have biphasic dose-dependent activity on angiogenesis, primary tumor growth, and metastasis. In fact, several angiogenesis modulators, such as α-IFN, endostatin, rosiglitazone, statins, chemotherapy (e.g., 5-fluorouracil, cisplatinum), bortezomib, enterostatin, integrin inhibitors, plasminogen activator-1, rapamycin, thrombospondin-1, TGF-α1, and TGF-α3, have been shown to exhibit a biphasic, U-shaped, or J-shaped dose-efficacy curve known as hormesis (16,17,(30)(31)(32)(33)(34). The sEHIs may be an addition to this growing class of angiogenesis modulators that exhibit a hormesis response.…”

Section: Cox-2/seh Dual Inhibitor Ptupb Inhibits Primary Tumor Growthmentioning

confidence: 99%

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Zhang

Panigrahy

Hwang

et al. 2014

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

114

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Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/ soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy.

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Section: Cox-2/seh Dual Inhibitor Ptupb Inhibits Primary Tumor Growthmentioning

confidence: 99%

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Zhang

Panigrahy

Hwang

et al. 2014

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

114

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“…[21][22][23] In order to determine whether the altered behavior of HemEPCs, HemECs, and cbEPCs is concentration dependent, we carried out the migration assay with varying ES concentrations. This dose-response analysis showed no significant changes in the migration rate of the cells upon treatment with 1 ng/mL to 10 g/mL ES (data not shown).…”

Section: Es Induces Increased Adhesion Migration and Proliferation mentioning

confidence: 99%

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Khan

Melero‐Martin

et al. 2006

Blood

111

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Infantile hemangiomas are composed of endothelial cells (ECs), endothelial progenitor cells (EPCs), as well as perivascular and hematopoietic cells. Our hypothesis is that hemangioma-derived EPCs (HemEPCs) differentiate into the mature ECs that comprise the major compartment of the tumor. To test this, we isolated EPCs (CD133 ؉ /Ulex europeus-I ؉ ) and mature ECs (CD133 ؊ /Ulex europeus-I ؉ ) from proliferating hemangiomas and used a previously described property of hemangioma-derived ECs (HemECs), enhanced migratory activity in response to the angiogenesis inhibitor endostatin, to determine if HemEPCs share this abnormal behavior. Umbilical cord bloodderived EPCs (cbEPCs) were analyzed in parallel as a normal control. Our results show that HemEPCs, HemECs, and cbEPCs exhibit increased adhesion, migration, and proliferation in response to endostatin. This angiogenic response to endostatin was consistently expressed by HemEPCs over several weeks in culture, whereas HemECs and cbEPCs shifted toward the mature endothelial response to endostatin. Similar mRNAexpression patterns among HemEPCs, HemECs, and cbEPCs, revealed by microarray analyses, provided further indication of an EPC phenotype. This is the first demonstration that human EPCs, isolated from blood or from a proliferating hemangioma, are stimulated by an angiogenesis inhibitor. These findings suggest that EPCs respond differently from mature ECs when exposed to angiogenic or antiangiogenic signals. IntroductionInfantile hemangioma, the most common tumor of infancy, is characterized by rapid proliferation of the endothelial cells followed by slow spontaneous involution. 1 This transition from the proliferating phase to the involuting phase represents a gradient of cellular activity from unregulated proliferation to apoptosis. The molecular events that control the evolution of hemangioma remain obscure. Both intrinsic and extrinsic anomalies have been suggested to underlie the primary defect. [2][3][4][5][6] Recent studies showing that hemangioma-derived endothelial cells (HemECs) are clonal provide support for an intrinsic defect. 4,6 We and others have identified endothelial progenitor cells (EPCs) in hemangioma tissue and circulating blood of patients with hemangiomas, respectively. 7,8 These findings suggest that a hemangioma may arise from the clonal expansion of an EPC.An angioblastic origin for hemangiomas has been envisioned for over a century. In 1863, Virchow 9 questioned whether hemangiomas represented sequestered embryonic mesoderm. Pack and Miller 10 suggested that hemangiomas arise from the localized growth of angioblastic cells. Similarly, Malan 11 imagined hemangiomas as an activation of dormant angioblasts. Histologic examination of hemangioma ECs reveals an immature phenotype with large nuclei and scant cytoplasm. 12 During the rapid growth phase of hemangiomas, syncytial EC hyperplasia, with and without lumens, is seen. In the involuting phase, hyperplasia diminishes and mature vascular channels with defined lumens become prominent. 1 C...

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“…34 Our finding of an antiendothelial effect over the range of endostatin concentrations achieved in NSC-conditioned medium is especially important in light of recent reports of a biphasic dose-reponse curve for the therapeutic efficacy of endostatin. 48,49 The concentrations of endostatin released into the medium correlate with the systemic concentrations of about 200 ng ml À1 endostatin reportedly sufficient to induce tumor suppression in mice. 50 In NSC/CYP2B6-eGFP, the forced expression of CYP2B6 resulted in intracellular activation of CPA and subsequent cell death.…”

Section: Endostatin or Cytochrome P450 In Glioblastoma Therapymentioning

confidence: 99%

Primary neural stem/progenitor cells expressing endostatin or cytochrome P450 for gene therapy of glioblastoma

et al. 2008

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Despite recent technical improvements in surgical excision techniques and adjuvant radio-and chemotherapy, the clinical outcome of patients with grade IV astrocytoma (glioblastoma) remains very poor, with a median survival of less than 12 months. A promising approach to therapy employs gene-engineered neural stem/progenitor cells (NSCs) as a cellular therapeutic delivery system, to track glioblastoma cells and deliver anticancer molecules. However, most results on their tumor tropism have been derived by immortalized NSCs. We now report that primary murine gene-engineered NSCs displayed in vivo tropism for glioblastoma cells. Ten days after injection into the brain, many NSCs continued to express the transgene and the NSC marker, nestin. NSCs transduced with a retroviral vector co-expressing a secretable form of human endostatin and eGFP (NSC/endo-eGFP) released potentially antiangiogenetic concentrations of endostatin into the culture medium. Conditioned medium of NSC/endoeGFP cells inhibited the growth of mouse pulmonary microvascular endothelial cells (PMVECs). A good correlation between endostatin levels and PMVEC growth inhibition was observed. In NSCs co-expressing cytochrome P450 2B6 (CYP2B6) and eGFP (NSC/CYP2B6-eGFP), the forced expression of CYP2B6 resulted in intracellular activation of CPA and subsequent cell death. In the presence of NSC/CYP2B6-eGFP, we observed CPA cytotoxicity to DsRed-expressing U87Mg glioma cells. In vivo treatment of intracranial GL-261 glioblastoma with NSC/endo-eGFP caused a 65% reduction in tumor size, compared to untreated control mice or mice treated with NSC/eGFP cells. Our data suggest that primary NSCs transduced with retroviral vectors expressing endostatin and/or CYP2B6 have a potential role in glioblastoma therapy.

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Endostatin therapy reveals a U-shaped curve for antitumor activity

Cited by 49 publications

References 43 publications

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin

Primary neural stem/progenitor cells expressing endostatin or cytochrome P450 for gene therapy of glioblastoma

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