Potential Relevance of Bell-Shaped and U-Shaped Dose-Responses for the Therapeutic Targeting of Angiogenesis in Cancer

Reynolds, Andrew R.

doi:10.2203/dose-response.09-049.reynolds

Cited by 101 publications

(79 citation statements)

References 138 publications

(180 reference statements)

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“…Data from pre-clinical and clinical studies in mice and humans showed administration of type 1 IFNs (IFN␣ and -␤) generally exert a linear dose response, whereas exogenous IFN␥ exhibits a "bell-shaped" dose-response curve (83). A "bell-shaped" dose response is characterized by induction of stimulatory effects at low doses until it reaches a summit point where additional dosing cause inhibitory activity and deleterious effects (84). These data suggest the function(s) of endogenous and exogenous IFNs are probably defined by the dynamics between systemic and local inflammatory environments.…”

Section: Ifn-mediated Chronic Inflammation Checkpoint Inhibitors Anmentioning

confidence: 87%

Current prospects of type II interferon γ signaling and autoimmunity

Green

Young

Valencia

2017

Journal of Biological Chemistry

142

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Edited by Charles E. SamuelInterferon ␥ (IFN␥) is a pleiotropic protein secreted by immune cells. IFN␥ signals through the IFN␥ receptor, a protein complex that mediates downstream signaling events. Studies into IFN␥ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFN␥ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFN␥ signaling biology and the functional roles of IFN␥ in the autoimmune response.According to the National Institutes of Health, autoimmune diseases (ADs) 3 are one of the top 10 leading causes of death in female children and women in all age groups up to 64 years of age (1). Excess secretion of IFNs has been associated with development of human ADs (2). Interferons (IFNs) comprise a family of proteins classified as type I (IFN-␣, -␤, -⑀, -, and -), type II (IFN-␥, herein IFN␥), and type III (IFN-1-4) that have pleiotropic roles in immunity, cancer biology, and autoimmunity (2). Here, we aim to provide a basic understanding of the functions of the type II IFN␥ and the IFN␥-signaling pathway (hereafter referred to as IFN signaling) in a contextual and timing perspective related to the autoimmune environment and the development of ADs.

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Section: Ifn-mediated Chronic Inflammation Checkpoint Inhibitors Anmentioning

confidence: 87%

Current prospects of type II interferon γ signaling and autoimmunity

Green

Young

Valencia

2017

Journal of Biological Chemistry

142

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“…A marked increase in microvessel formation at lower doses between 0.625-1.25 µM was also observed. This bell-shaped effect (hormesis) is common in anticancer agents (15,42) which suggests the importance of maintaining the SFN at high concentrations (>5 µM) for cancer chemoprevention or treatment. These tube formation results were consistent with the cell viability data that showed that SFN inhibited the growth of ECs at concentrations of 5-20 µM while at low concentrations of 0.625-2.5 µM, SFN promoted cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…The binding to VEGF receptor is a crucial step in initiation of EC proliferation, migration and differentiation during angiogenesis (13,14). The VEGF signalling system has been suggested as a highly 'druggable' target and potent inhibitors of the VEGF signalling pathway have been used clinically including bevacizumab, sunitinib and sorafeib (15)(16)(17). To date, targeting the HIF/VEGF-VEGFR axis has been a promising strategy for cancer therapy (18).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

et al. 2017

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Abstract. Aberrant neovascularization supports nutrients and the oxygen microenvironment in tumour growth, invasion and metastasis. Recapitulation of functional microvascular structures in vitro could provide a platform for the study of vascular conditions. Sulforaphane (SFN), an isothiocyanate, has been reported to possess chemopreventive properties. In the present study, the effects of SFN on cell proliferation and tubular formation have been investigated using endothelial cells (ECs) and pericytes in coculture. SFN showed a dosedependent inhibition on the growth of ECs and pericytes with IC 50 values 46.7 and 32.4 µM, respectively. SFN (5-20 µM) inhibited tube formation in a 3D coculture although a lower dose (1.25 µM) promoted 30% more endothelial tube formation than control. Moreover, SFN affected intercellular communication between ECs and pericytes via inhibition of angiogenic factor such as vascular endothelial growth factor (VEGF) expression in pericytes. However, the expression of its receptor (VEGFR-2) was found significantly increased in ECs. These effects were associated with downregulation of prolyl hydroxylase domain-containing protein 1 and 2 (PHD1/2) and activation of hypoxia-inducible factor-1 (HIF) pathway by SFN. Furthermore, thioredoxin reductase-1 was also upregulated by SFN treatment, suggesting that antioxidant and redox regulation are involved in angiogenesis. Taken together, the results of the present study suggest that SFN differentially regulates endothelial cells and pericytes disrupting their interplay through the VEGF-VEGFR signalling pathway. Anti-angiogenesis property of SFN indicates that it has potential role as an anticancer agent. IntroductionAngiogenesis, the growth of new capillary blood vessels, is a normal and vital process in growth, development and wound healing. However, it is also a fundamental step in the growth of tumours. Nutrients and oxygen, supplied by the blood vessels into the tumours, are essential for the growth and progression of malignant tumours beyond the size of 1-2 mm 3 (1). Newly formed blood vessels can facilitate cells escaping through leakage from primary tumour sites to metastasize, the major cause of mortality for cancer patients. Anti-angiogenesis has been recognized as valuable therapy in treatment of various metastatic cancers since the theory was first proposed by Folkman (2,3). Tumour angiogenesis is believed to be regulated by the interactions between pro-angiogenic and anti-angiogenic factors in the tumour microenvironment (4). Angiogenic response is a dynamic process requiring a series of fine-tuned angiogenic signalling and molecular events. Hypoxia is the common inducer of angiogenesis in the core of large tumours stimulating the release of pro-angiogenic factors to promote endothelial cell proliferation, migration, differentiation and self-assembly into vascular-like structures. Subsequently, perivascular cells are recruited to form mature and stable vessels (5).The interaction between endothelial cells (ECs) and pericytes (PVCs) has g...

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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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Potential Relevance of Bell-Shaped and U-Shaped Dose-Responses for the Therapeutic Targeting of Angiogenesis in Cancer

Cited by 101 publications

References 138 publications

Current prospects of type II interferon γ signaling and autoimmunity

Current prospects of type II interferon γ signaling and autoimmunity

Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes

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

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