2-2--(hydroxynitrosohydrazono)bis-ethanamine and Ovarian-Neoplasms

Ovarian cancer chemoresistance, both intrinsic and acquired, is the main obstacle in improving the outcome of anticancer therapies. Therefore the development of new treatment strategies, including the use of new compounds that can support the standard therapeutics is required. Among many candidates, nitric oxide (NO) donors, agents with multivalent targeted activities in cancer cells, are worth considering. The aim of this study was evaluation of SPER/NO and DETA/NO ability to enhance cisplatin cytotoxicity against different ovarian cancer cell lines. Obtained data indicate that NO donors action varies between different cancer cell lines and is strongest in low aggressive and cisplatin sensitive cells. While statistically significant, the enhancement of cisplatin cytotoxicity by NO donors is of low magnitude. The rise in the percentage of late apoptotic/necrotic ovarian cancer cells may suggest that NO donors enhancement action might be based on the cellular ATP depletion. Nevertheless, no significant impact of the NO donors, cisplatin or their combination on the expressions of ABCB1, BIRC5 and PTEN genes has been found. Although our data puts the therapeutical potential of NO donors to aid cisplatin action in question it may also point out at the further approach to utilize these compounds in therapies.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Female; Humans; Inhibitor of Apoptosis Proteins; Nitric Oxide; Nitric Oxide Donors; Ovarian Neoplasms; PTEN Phosphohydrolase; Spermine; Survivin; Triazenes

The most important factors involved in tumor metastasis and angiogenesis are metalloproteinases (MMPs), vascular endothelial growth factor, and multifunctional transforming growth factor β1. These factors are responsible for extracellular matrix degradation, induction of vascular permeability, and enhancement of tumor cells' invasion and metastasis. Elevated expression and secretion of the above-mentioned factors are correlated with the higher aggressiveness of tumors and low patient survival for example, patients with ovarian cancer. Therefore, regulation of the expression, secretion, and activity of these factors is still considered a potent target for therapeutic intervention in cancer patients. Nitric oxide (NO) donors belong to the class of agents with multivalent targeted activities in cancer cells and are considered potential anticancer therapeutics. Our studies have shown that NO donors such as spermine/NO and diethylenetriamine/NO decrease the secretion of vascular endothelial growth factor-A from the OVCAR-3 ovarian cancer cell line, but not from the SK-OV-3 ovarian cancer cell line. The release of MMP-2 from both cell lines was reduced in a soluble guanylate cyclase-dependent manner by spermine/NO and diethylenetriamine/NO. Nevertheless, MMP-2 activity was only affected in SK-OV-3 cells. Both NO donors reduced the transmigration of the ovarian cancer cell lines. We did not observe any significant effect of spermine/NO and diethylenetriamine/NO on mRNA expression of the tested aggressiveness factors. In conclusion, our data indicated that NO donors reduced the metastatic potential of ovarian cancer cells, but its impact is rather low and requires high concentrations of donors. Moreover, both the tested cell lines differed in the susceptibility to NO donors.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; Female; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Nitric Oxide Donors; Nitroso Compounds; Ovarian Neoplasms; Spermine; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

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.

Topics: Aminosalicylic Acids; Apoptosis; Benzenesulfonates; Cell Line, Tumor; Cell Survival; Female; Humans; Nitric Oxide Donors; Nitrites; Ovarian Neoplasms; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-akt; Signal Transduction; Spermine; STAT3 Transcription Factor; Statistics, Nonparametric; Triazenes