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.
Highlights
From the first studies on the effect of nitric oxide (NO) in cancer biology, this mediator emerged as a biphasic modulator, behaving both as an antineoplastic and proneoplastic stimulus [1]
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
To test the effect of novel NO donor, human lung carcinoma cells A549 cells were exposed for 72 h to Ni(SalPipNONO) and DETA/NO used in a wide range of concentrations (0.001–1 mM) and cell viability was assessed by the MTT assay
Summary
From the first studies on the effect of nitric oxide (NO) in cancer biology, this mediator emerged as a biphasic modulator, behaving both as an antineoplastic and proneoplastic stimulus [1]. The established biochemical/cellular events elicited by NO against tumor development are essentially inhibition of cell proliferation and proapoptotic events, and vascular effects including anti-angiogenesis. NO released by NO donors or nitric oxide synthase (NOS) has been suggested to activate p53 via DNA damage by peroxynitrite (ONOO–) [5,6,7]. The use of NO donors can improve vascular flow, and anticancer drug delivery in hypoxic tissue, favoring the penetration of chemotherapy in tumor tissue and improving their cytotoxic effects [8,9,10]. An increase in response to radiotherapy [10, 11] and chemotherapy [12, 13] has been reported
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