The metal-nonoate Ni(SalPipNONO) inhibitsin vitrotumor growth, invasiveness and angiogenesis

// Valerio Ciccone 1, * , Martina Monti 2, 3, * , Enrico Monzani 3, 4 , Luigi Casella 3, 4 and Lucia Morbidelli 1, 3 1 Department of Life Sciences, University of Siena, Siena, Italy 2 Department of Molecular Medicine and Development, University of Siena, Siena, Italy 3 Noxamet Ltd, Milan, Italy 4 Department of Chemistry, University of Pavia, Pavia, Italy * These authors contributed equally to these work Correspondence to: Lucia Morbidelli, email: lucia.morbidelli@unisi.it Keywords: nitric oxide donor; lung cancer cells; apoptosis; angiogenesis; vascular endothelial growth factor Received: October 18, 2017      Accepted: January 25, 2018      Published: January 30, 2018 ABSTRACT Nitric oxide (NO) exerts conflicting effect on tumor growth and progression, depending on its concentration. We aimed to characterize the anti-cancer activity of a new NO donor, Ni(SalPipNONO) belonging to the class of metal-nonoates, in epithelial derived tumor cells, finally exploring its antiangiogenic properties. Tumor epithelial cells were screened to evaluate the cytotoxic effect of Ni(SalPipNONO), which was able to inhibit cell proliferation in a dose dependent manner, being more effective than the commercial DETA/NO. The human lung carcinoma cells A549 were chosen as model to study the anti-cancer mechanisms exerted by the compound. In these cells, Ni(SalPipNONO) inhibited clonogenicity and cell invasion, while promoting apoptosis. The antitumor activity was partly due to NO-cGMP dependent pathway, contributing to reduced cell number and apoptosis, and partly to the salicylaldehyde moiety and reactive oxygen species (ROS) activated ERK1/2 signaling converging on p53 dependent caspase-3 cleavage. An additional contribution by downstream cycloxygenase-2 (COX-2) derived cyclopentenones may explain the tumor inhibitory activities. As NO has been described to affect tumor angiogenesis, we checked this activity both on tumor and endothelial cell co-cultures and in Matrigel in vivo assay. Our data document that Ni(SalPipNONO) was able to both reduce angiogenic factor expression by tumor cells acting on hypoxia inducible factor-1α (HIF-1 α) level, and endothelial cell functions related to angiogenesis. Collectively, these data confirm the potential use of NO donors and in particular Ni(SalPipNONO) acting through multiple mechanisms, as an agent to be further developed to be used alone or in combination with conventional therapy.