Reduction of tumor angiogenesis induced by desmopressin in a breast cancer model

Abstract

Desmopressin (DDAVP), a synthetic peptide analog of vasopressin, is a safe antidiuretic and hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor. It is known that DDAVP can inhibit progression of residual metastatic cells and also improves chemotherapy effects in preclinical breast cancer models. Here, we explored the effects of DDAVP on tumor angiogenesis using the aggressive F3II mammary carcinoma in syngeneic Balb/c mice. Intravenous administration of the compound (2 μg/kg) markedly decreased vascularization of growing subcutaneous tumors, as well as inhibited the early angiogenic response around intradermal inoculation sites. In vitro studies confirmed the presence of vasopressin V2 receptors on F3II cells and a modest antiproliferative activity of DDAVP. Interestingly, conditioned media from F3II monolayers exposed to low doses of DDAVP (100 nM) significantly increased angiostatin formation in the presence of purified plasminogen. Such increase was associated with an enhancement of tumor-secreted urokinase-type plasminogen activator, suggesting the proteolytic conversion of plasminogen to angiostatin in vitro. Similar results were observed with the MCF-7 human breast carcinoma, a cell line known to express the vasopressin V2 receptor. No direct effects of DDAVP (100 nM–1 μM) were found on capillary-like tube formation by human microvascular cells HMVEC. Our studies showed that DDAVP induces anti-angiogenic effects that may be associated with the generation of angiostatin by tumor cells. Further preclinical studies with DDAVP and other vasopressin analogs are warranted to determine their potential in cancer management.

Effect of Combination therapy of Desmopressin and Docetaxel on prostate cancer cell DU145 proliferation, migration and growth

“…We attribute the tumor volume reduction to apoptosis induction. It could also be related to reduced angiogenesis, as previously demonstrated with breast cancer cells [1]. Desmopressin has been known to stimulate endothelial cells to release Von Willebrand factor (VWF) [12].…”

“…VWF plays a protective role against tumor cell dissemination and may cause apoptosis of micro metastatic foci. Data supporting this was collected from breast cancer in vitro and in vivo models, supporting anti angiogenic as well as cytostatic effects [1,14], and reduction of cancer cells in distant metastasis [14]. Endothelial V2 receptor activation could contribute to tumor reduction via angiogenesis inhibition and reduced VWF levels in tumor microenvironment.…”

“…Desmopressin is a well-known synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis both in vitro and in vivo models in breast cancer [1]. Docetaxel, a well established anti-mitotic and chemotherapeutic agent, acts by reversibly binding microtubules.…”

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

“…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. Treatments with Abner, instead of administering V2 receptor agonist proposed by Garona et al [2015] for breast cancer, would have the advantage of not exacerbating the condition of SIADH present in many cases of small-cell lung cancer.…”

Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial

“…The potent hemostatic effects of dDAVP at relatively low doses of 0.2-0.3 µg/kg allows its use in the management of bleeding disorders and as a blood-saving agent during surgical procedures [8]. In addition, preclinical evidence has been accumulating on the antiangiogenic and antimetastatic properties of dDAVP at a higher dose range of 1-2 µg/kg in animal models of breast, prostate and colorectal cancer [9][10][11][12][13]. A recent clinical trial in breast cancer patients administered with perioperative infusions of dDAVP demonstrated a reduced intrasurgical bleeding with increasing doses of the compound.…”