The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models

Garona, Juan; Pífano, Marina; Orlando, Ulises Daniel; Pastrián, María Belén; Iannucci, Nancy B.; Ortega, Hugo Héctor; Podestá, Ernesto J.; Gomez, Daniel E.; Ripoll, Giselle Vanina; Alonso, Daniel F.

doi:10.3892/ijo.2015.2952

Cited by 31 publications

(56 citation statements)

References 49 publications

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“…Nevertheless, Zhu and Weiss [1998] found that a similar, but inherited, truncated vasopressin receptor molecule referred to the Utah mutation when coexpressed with wild-type V2 receptor dimerized with this form and effectively inhibited all downstream activity. Since we, and others [North, 2000;North et al 1998ab;Taylor et al, 1990;Ripoll et al 1990;Garona et al, 2015], have demonstrated that vasopressin action through V2 receptors is inhibitory to the growth of solid tumors, we have concluded that tumors probably manufacture AbnV2R as a null receptor to impair such growth inhibition. Since Alonso and coworkers [Ripoll et al, 2013;Garona et al,2015] have shown that activation of tumor V2 receptors seems to impair angiogenesis and tumor metastasis as well as retard growth of breast cancer, it is conceivable that all these mechanisms could also play some role in the inhibitory actions of Abner if the antibody internalizes and removes the null receptor and allows influences by tumor-generated vasopressin to be increased through normal V2 receptors.…”

Section: Discussionmentioning

confidence: 56%

New Agents for Treatment of Recurrent Small-Cell Cancer: Tumor-Specific Abnormal Vasopressin V2 Receptor Antibodies

North¹

2016

IMR

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We earlier demonstrated that small-cell lung cancer (SCLC) not only expresses a normal form of vasopressin V2 receptor but also an abnormal form, through alternate splicing, that lacks the seventh transmembrane region (named AbnR2). This tumor-specific abnormal receptor is expressed at the surface of cells and can be targeted by antibodies directed against a unique C-terminal region. Immunocytochemistry reveals AbnR2 is common to all or most small-cell lung tumors. Our generated mouse monoclonal antibody was found to decrease cell viability in vitro and promote apoptotic cascades. This mouse anti-AbnR2 antibody, and a humanized form derived from it, were each found to reduce the growth of SCLC xenografts representing recurrent disease in nu/nu mice, and to have synergistic, tumor anti-proliferative effects when used with cyclophosphamide, but not cisplatin, in completely inhibiting growth. Possible mechanisms might involve normal vasopressin V2 receptors.

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Section: Discussionmentioning

confidence: 56%

New Agents for Treatment of Recurrent Small-Cell Cancer: Tumor-Specific Abnormal Vasopressin V2 Receptor Antibodies

North¹

2016

IMR

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“…Cell cycle distribution. Cell cycle phase distribution and hypodiploid population quanti cation in starved OSA cells following a 24 h PPN (50 µM) treatment was evaluated by ow cytometry as previously reported [25] (for detailed methodology see Additional le 1. Supplementary methods).…”

Section: Methodsmentioning

confidence: 99%

“…Clonogenic growth. Effect of PPN (1, 10 or 50 µM) on OSA colony forming ability was assessed using a 7-d clonogenic assay, as previously reported [25] (for detailed methodology see Additional le 1.…”

Section: Methodsmentioning

confidence: 99%

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

Solernó¹,

Sobol²,

Capobianco³

et al. 2020

Preprint

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Background: Osteosarcoma is still associated with poor response to therapy and alarmingly elevated mortality rates, especially in developing countries, highlighting the urgent need of novel therapeutic strategies. Given that β-adrenergic receptor (β-AR) signaling regulates many cellular processes involved in the initiation and progression of cancer, multiple efforts have been made to repurpose non-selective β-blocker propranolol in oncology. Considering the unsatisfied clinical needs of osteosarcoma, we evaluated the in vitro and in vivo antitumoral activity of propranolol as a monotherapy or in combination with metronomic chemotherapy, in β-AR-expressing human osteosarcoma cells. Methods: In vitro anti-osteosarcoma effects of propranolol were assessed on high-density cell growth, chemotaxis, colony-forming ability and three-dimensional spheroids. Cell cycle phase distribution and apoptosis were evaluated using flow cytometry analysis, and quantification of hypodiploid cell population and TUNEL labelling, respectively. Propranolol addition to chemotherapy was evaluated in vitro and in human osteosarcoma xenografts generated in athymic mice.Results: Propranolol significantly impaired MG-63 and U-2 OS cellular growth in a concentration range of 10-100 µM (IC50 ≈ 45µM) and was capable of blocking in vitro protumoral effects triggered by catecholamines. Cytostatic activity of propranolol was associated to reduced mitosis and G0/G1 cell cycle, but not to apoptosis induction. Moreover, β-blocker drastically reduced colony formation, spheroid progression and migration of osteosarcoma cells. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agents methotrexate or cisplatin. In vivo, treatment with propranolol (10 mg/kg i.p.), alone and especially in addition to non-interrupted low-dose cisplatin (2 mg/kg i.p.), markedly abrogated xenograft progression, reducing tumor growth rates by 25 or 70%, respectively. After histological analysis, propranolol and cisplatin combined therapy resulted in low tumor mitotic index and increased tumor necrosis. Conclusions: Considering its robust antitumoral effects, β-AR antagonization using β-blocker propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness, in addition to chemotherapy. Propranolol could be proposed as a co-adjuvant agent for the management of osteosarcoma, especially in low- and middle-income countries where access to treatment resources are limited. Further preclinical and clinical studies of propranolol repurposing in osteosarcoma are warranted.

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“…Наряду с опухолями, тромбоциты и эндотелиоциты относятся к наименее исследованным клеточным мишеням вазопрессина. Можно предположить, что в ряде случаев, в том числе в опухолях, центральная нейрогормональная регуляция синхронизирует в тканях пролиферативный ответ на вазопрессин (Garona et al, 2015). Активная пролиферация тканей всегда сопровождается реорганизацией локальной системы кровоснабжения (Maharaj et al, 2006).…”

Section: активация тромбоцитов и эндотелиоцитовunclassified

Noncanonical effects of vasopressin in angiogenesis

Khegai

2019

Vestn. VOGiS

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The molecular action of vasopressin depends on the localization of hormonal receptors. The basic physiological effects of vasopressin are manifested in the blood vasculature, renal inner medulla and brain. To date, new information concerning the tissue-specific spreading of vasopressin receptors has been accumulated, and it needs to be summarized. Platelets and endotheliocytes expressing V1a and V2 receptor types, respectively, are related to less investigated targets of the hormone. Vasopressin induces the initial reversible stage of platelet activation, required for interaction with intercellular matrix proteins. Platelet adhesion on endothelium activates cellular secretion of growth factors and enzymes for intercellular matrix glucosamine metabolism. Platelet hyaluronidase HYAL2 hydrolyses high-molecular hyaluronic acid to shorter fragments. Unlike intact hyaluronic acid with a molecular weight of several megadaltons, generally showing distinctive antiangiogenic properties, intermediate fractions of hyaluronan hydrolysis in a range from 2.5 to 200 kilodaltons have a stimulating effect on angiogenesis. Intercellular contacts between platelets and endotheliocytes are stabilized due to adhesive transmembrane glycoprotein PECAM-1 interaction. Resulting PECAM-1 heterodimers acquire conformation with high affinity to integrins αvβ3. Integrin activation forms contact links between endothelium and fibrillar proteins. Activated endotheliocytes secrete von Willebrand factor and P-selectin. These proteins are accumulated in Weibel–Palade bodies. Vasopressin stimulates cAMP-dependent ACAP-regulated exocytosis of Weibel–Palade bodies. von Willebrand factor possesses adhesive properties and additionally accelerates interaction of cells with the intercellular matrix. Adhesion on fibrillar collagen and membrane glycoproteins in cooperation with effects of PECAM-1–αvβ3 integrin complexes fixes cell aggregates in the surrounding interstitium and promotes proliferating endotheliocyte migration in according to the direction of local growth factor gradients during angiogenesis. Neurohormonal regulation of platelet and endotheliocyte secretory activity functionally link proliferation and migration of endotheliocytes during angiogenesis and integrate it according to the adaptive capacity of the entire organism.

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The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models

Cited by 31 publications

References 49 publications

New Agents for Treatment of Recurrent Small-Cell Cancer: Tumor-Specific Abnormal Vasopressin V2 Receptor Antibodies

New Agents for Treatment of Recurrent Small-Cell Cancer: Tumor-Specific Abnormal Vasopressin V2 Receptor Antibodies

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

Noncanonical effects of vasopressin in angiogenesis

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