Introduction: Nitric oxide-releasing nonsteroidal antiinflammatory drugs (NO-NSAIDs) are potentially an important class of chemopreventive agents against cancer. They consist of a traditional NSAID attached to an NO releasing moiety through a chemical spacer. It had previously been shown that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer (JPET 312:978-988, 2005). Hence, we synthesized an NO-releasing arylpropionic acid NSAID, comprising an aromatic spacer and evaluated it against several human cancer cell lines as well as an animal model of colon carcinogenesis.
Methods: FBN: synthesized, purified, NMR and mass spectrometry verified by us; human cancer cell lines: HT-29 (colon, COX-1 and -2 positive); HCT 15 (colon, COX null); MIA PaCa-2 (pancreas, COX null); BxPc-3 (pancreas, COX-1 and -2 positive); A549 (lungs); A-431 ( skin); LNCaP (prostate); MCF-7 (breast); SSC-25 (tongue squamous cell carcinoma); and HeLa, Caski (cervix). Cell growth: MTT; cell cycle phase distribution: flow cytometry; apoptosis: subdiploid (sub-G0/G1) peak in DNA content histograms; proliferation: PCNA. In vivo: six-week-old female C57BL/6J APCMin/+ mice and the corresponding C57BL/6J+/+ wild type mice (N = 10 animals/group). Each mouse was treated via oral administration by gavage as follows: group 1, wild type controls treated with vehicle; group 2, wild type controls treated with FBN (100 mg/kg/day); group 3, Min mice treated with vehicle; group 4, Min mice treated with FBN (100 mg/kg/day). After 21 days of treatment all animals were euthanized and their small intestine was dissected. Tumors were counted under a magnifying lens.
Results: FBN inhibits the growth of colon, pancreas, lung, skin, prostate, breast, tongue and cervical cancer cells, being up to 20-fold more potent than flurbiprofen. This effect is due to: a) cell kinetics: inhibition of proliferation (PCNA), b) induction of apoptosis (multiple criteria) and c) in general blocking the G1 to S cell cycle transition. Animal studies: there were no signs of overt toxicity including gastrointestinal toxicity from FBN. The number of tumors were reduced by 95.6% (number of tumors in controls = 32.1 ± 6.4; treated animals = 1.4 ± 2.8, p < 0.001, mean ± SD).
Conclusions: These findings establish a strong inhibitory effect of FBN in various human cancer lines, an effect which is modulated through parameters important in determining cellular mass. Our findings also show a strong inhibitory effect in intestinal carcinogenesis in the Min mouse. Taken altogether, these data suggest that FBN merits further evaluation as a chemopreventive and potentially chemotherapeutic agent.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA