Nitric oxide donors: spermine/NO and diethylenetriamine/NO induce ovarian cancer cell death and affect STAT3 and AKT signaling proteins.

The important features of cancer cells are uncontrolled growth and proliferation, as well as the ability to metastasis. These features depend mainly on the constant overexpression and activity of various cell signaling proteins, such as signal transducer and activator of transcription 3 (STAT3) and serine-threonine protein kinase AKT proteins. Nitric oxide (NO) has the potential of being anti-tumoral agent, however the exact character of anti-tumoral action of NO is still a matter of debate. In our research we used two NO donors, belonging to NONOates family, with different half-life times: spermine nitric oxide complex hydrate (SPER/NO t1/2=39min) and diethylenetriamine nitric oxide adduct (DETA/NO, t1/2=20h). We evaluated the cytotoxic effect of aforementioned NO donors on SK-OV-3 and OVCAR-3 ovarian cancer cell lines, as well as their effect on posttranslational modification of STAT3 and AKT proteins in these cells. We found that both NO donors present cytotoxic activity on the cancer cell lines, mainly through the induction of apoptosis. What is more, at the high concentration and longer exposure time they were also capable of inducing late apoptosis/necrosis. Both NO donors inhibited STAT3 and AKT3 proteins phosphorylation and down regulated their cytosolic levels, with DETA/NO being stronger inhibitor. We suggests, that NO donors have the potential to act as anti-tumoral agent through inhibiting cancer cell signaling and reducing their viability.