Non-steroidal anti-inflammatory drugs (
NSAIDs) have repeatedly shown to be effective in
tumor prevention, but important side-effects limit their wide clinical use.
Nitric oxide-releasing derivatives (NO-
NSAIDs) are a promising class of compounds synthesized by combining a classic
NSAID molecule with an NO-releasing moiety to counteract side-effects. These new chemical entities exhibit a significantly higher activity and much lower toxicity with respect to the parental
drug. In the present paper, we report the results obtained from in in vitro experimental systems aimed to evaluate the activity and mechanisms of action of the novel NO-releasing
aspirin derivative,
NCX 4040. The in vitro studies were carried out on a panel of human colon (LoVo, LoVo Dx, WiDr, LRWZ), bladder (HT1376, MCR), and pancreatic (Capan-2, MIA PaCa-2, T3M4)
cancer cell lines. With regard to
colon cancer,
NCX 4040 activity was also investigated in vitro in combination with drugs currently used in clinical practice and was validated in vivo on
tumor-bearing mice xenografted with the aforementioned
colon cancer cell lines. The in vitro studies showed a high cytotoxic activity of
NCX 4040 in all
tumor histotypes and demonstrated the pivotal role of the NO component in
drug activity. It was also observed that
NCX 4040 exerts a pro-apoptotic activity via a mitochondria-dependent pathway. Moreover, the in vivo studies on xenografted mice further confirmed the antitumor efficacy and low toxicity of
NCX 4040 in
colon cancer and highlighted its role as sensitizing agent of
oxaliplatin cytotoxicity.