Although non steroidal antiinflammatory drugs (
NSAIDs) have been shown to be effective as chemopreventive agents, important side-effects limit their clinical use. A promising novel class of drugs,
nitric oxide-donating
NSAIDs (NO-
NSAIDs), has been found to be more active than classical
NSAIDs. This study explored the effect of the NO-donating
aspirin derivative,
NCX 4040, on three human pancreatic
adenocarcinoma cell lines (Capan-2, MIA PaCa-2 and T3M4).
NCX 4040 activity was compared with that of
NCX 4016 (an NO(2)-positional isomer of
NCX 4040), SNAP (a standard NO-releasing molecule),
NCX 4042 (denitrated analog of
NCX 4040), and
aspirin.
NCX 4040 showed a striking cytocidal activity in all cell lines, already inducing significant percentages of apoptotic cells
at 10 muM in Capan-2 cell lines. This study focused on the
biological mechanisms of sensitivity and resistance to
NCX 4040, highlighting that the cytotoxic action of this
drug may be due to the hyperexpression of Bax, its translocation to the mitochondria, the release of
Cytochrome C, and the activation of caspases-9 and -3, overall in a p53-independent manner. Moreover, the use of a specific
COX-2 inhibitor (
NS 398) in the experimental models showed that COX-2 hyperexpression could partially explain the resistance mechanisms to
NCX 4040.