The metal-nonoate Ni(SalPipNONO) inhibits in vitro tumor growth, invasiveness and angiogenesis

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.