Search of Vasopressin Analogs with Antiproliferative Activity on Small-Cell Lung Cancer: Drug Design Based on Two Different Approaches

Abstract

Combination of these strategies could provide the basis for future studies for the development of improved compounds with potential therapeutic applications.

Preclinical Efficacy of [V4 Q5 ]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer

“…In line with these findings, complete reversal of in vitro [V 4 Q 5 ]dDAVP activity after AVPR2 chemical blockade was also reported by our group in highly aggressive breast cancer cells [15]. Moreover, we recently showed that after siRNA-mediated knockdown of AVPR2 expression in human lung carcinoma cells, [V 4 Q 5 ]dDAVP antiproliferative effects were significantly attenuated, confirming AVPR2-dependency of [V 4 Q 5 ]dDAVP cytostatic action in malignant cells [5,27]. In this experimental setting, the development of a CRC cell model with AVPR2 gene knockout or knockdown is highly interesting, and should be pursued with the aim of corroborating previously described findings.…”

Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma

“…Using the AVPR2-expressing MG-63 model, we showed that, in accordance with previously reported preclinical studies (14,(16)(17)(18)(23)(24)(25), in vitro dDAVP treatment reduced osteosarcoma cell growth and chemotaxis, and cytostatic activity was related to increased cAMP intracellular levels upon AVPR2 stimulation. Furthermore, inhibition of cAMP-degrading phosphodiesterases by addition of rolipram enhanced the antiproliferative effects of dDAVP in osteosarcoma cells.…”

“…dDAVP has been used as a blood-saving agent for nearly 50 years in patients with bleeding disorders or undergoing complex surgeries characterized by large blood loss (11). This compound is a 1st generation synthetic analog of the vasopressin hormone (AVP) and acts as a selective agonist for the vasopressin membrane receptor type 2 (AVPR2) expressed in microvascular endothelium (12) and several transformed tissues, including breast (13)(14)(15), prostate (16), lung (17) and colorectal cancer (18,19). Agonistic stimulation of vascular AVPR2 is associated with a cyclic adenosine monophosphate (cAMP)-mediated acute release of several hemostatic factors into the bloodstream, including factor VIII, tissue-type plasminogen activator and von Willebrand factor (VWF).…”

“…VWF is a multifaceted blood glycoprotein involved in different biological processes such as coagulation, vascular normalization, cancer cell apoptosis and metastatic resistance (20)(21)(22). Preclinical studies by our research group and others using breast, colorectal, and lung cancer models reported that activation of tumor AVPR2 by dDAVP triggers antiproliferative signaling mechanisms after cAMP/cAMP-dependent protein kinase (PKA) axis activation, resulting in cell cycle arrest and decreased cell survival and growth (14,(16)(17)(18)(23)(24)(25). Cytostatic activity showed to be AVPR2-dependent as dDAVP effects on malignant cells were completely reverted after AVPR2 phamacological blockade or siRNA-mediated receptor depletion was performed (16,23,24).…”

MAPK Pathway: a Potential Target for the Treatment of Non-small-cell Lung Carcinoma

“…Lung cancer is a leading cause of cancer-associated death worldwide [1,2]. Explanation of the molecular biology and pathogenesis of lung cancer is essential for the design of a potential treatment for patients [3,4]. Non-small-cell lung carcinoma (NSCLC) is a complex process concerning interruption of cell proliferation, cell differentiation, apoptosis and various molecular mechanisms.…”