NCX 4040, an NO-donating acetylsalicylic acid derivative: efficacy and mechanisms of action in cancer cells.
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.
Tesei
Anna
A
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Via Maroncelli 40, 47014 Meldola, FC, Italy. anna.tesei@ausl.fo.it
Zoli
Wainer
W
Fabbri
Francesco
F
Leonetti
Carlo
C
Rosetti
Marco
M
Bolla
Manlio
M
Amadori
Dino
D
Silvestrini
Rosella
R
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020030:Nitric Oxide Donors; D009574:Nitro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use
C498045:NCX 4040; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009944:Organoplatinum Compounds; D011725:Pyridines; C431073:oxiplatin; D001241:Aspirin