In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala ؉ TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A-induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin ␣3␤1 expression, expression of a dominant negative protein tyrosine phosphatase Shp-1 mutant, administration of the protein tyrosine phosphatase inhibitor orthovanadate, or the adenylate cyclase inhibitor SQ22536. This TIMP-2-mediated inhibition of vascular permeability involves an integrin ␣3␤1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association, as evidenced by using siRNAs to integrin ␣3␤1 and Shp-1, or treatment with Shp-1 inhibitor NSC87877 and protein kinase A inhibitor H89. Our results demonstrate the potential utility for TIMP-2 in cancer therapy through "normalization" of vascular permeability in addition to previously described antiangiogenic effects. (Blood. 2012;120(24):4892-4902) IntroductionTumor-associated angiogenesis is critical for tumor progression and metastasis. The central role of vascular endothelial growth factor-A (VEGF-A) in this process is evidenced by the development and approval of bevacizumab, a VEGF-A neutralizing antibody, for therapy in several human cancers. VEGF-A-induced angiogenesis is often accompanied by increased vascular permeability, which can result in fibrin deposition and may facilitate tumor cell extravasation enhancing metastasis formation. 1 The resulting vascular leak has also been shown to increase interstitial pressure within the tumor, decrease tumor blood flow, and hinder drug delivery to the tumor. Indeed, it has been proposed that VEGF-axis targeted therapies may result in "normalization" of tumor vasculature improving chemotherapeutic delivery and decreasing hypoxia, resulting in enhanced radiosensitivity. 2,3 Vascular permeability can be modulated by the phosphorylation, cleavage, and internalization of vascular endothelial (VE)-cadherin. [4][5][6] Tyrosine phosphorylation of the cadherin-catenin complexes is regulated by the activities of protein tyrosine phosphatases and src-family kinases. 7-11 Inhibition of tyrosine phosphorylation of VE-cadherin increases the stability of adherens junctions and improves vascular barrier function. Matrix metalloproteinase (MMP)-mediated cleavage of VE-cadherin may promote vascular permeability and cell proliferation by dissociating cadherin-catenin complex and disrupting cell-cell adhesion. [12][13][14][15] In contrast, it is widely recognized t...

Following our report that A 3 adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1′homologated adenosine analogues 4a−4t, as dual PPARγ/δ modulators without AR binding. Removal of binding affinity to A 3 AR was achieved by 1′homologation, and PPARγ/δ dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPARγ/δ but lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγ affinity, indicating that the C2 position defines a pharmacophore for selective PPARγ ligand designs. PPARγ/δ dual modulators functioning as both PPARγ partial agonists and PPARδ antagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.

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Triple-negative breast cancers (TNBCs) are hard-to-treat breast tumors with poor prognosis, which need to be treated by chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in proliferation, metastasis, and invasion of cancer cells. Therefore, research on searching for promising compounds with metabolism that suppress phosphorylation or transcription of STAT3 in TNBC cells is important. Farfarae Flos is well known as a traditional medicine for treating inflammation. However, few studies have shown that sesquiterpenoids from Farfarae Flos have an anticancer effect. In this study, efficient separation methods and an MTT assay were conducted to isolate an anticancer compound from Farfarae Flos against TNBC MDA-MB-231 cells. Here, 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a compound isolated from Farfarae Flos showed a potent cytotoxic effect on MDA-MB-231 cells. ECN inhibited JAK–STAT3 signaling and suppressed the expression of STAT3 target genes. In addition, ECN induced apoptosis through both extrinsic and intrinsic pathways. Furthermore, we investigated that ECN inhibited the growth of tumors by intraperitoneal administration in mice injected with MDA-MB-231 cells. Therefore, ECN can be an effective chemotherapeutic agent for breast cancer treatment.