Abstract 1353: Hydrogen sulfide-releasing naproxen inhibits HT-29 human colon cancer cell growth: Modulation of NF-κB

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: Chronic inflammation is widely recognized as an underlying etiological factor in carcinogenesis; there is enough evidence to support the use of non-steroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents. However, their wide use is precluded due to significant toxicity. Recently, a new class of hydrogen sulfide-releasing NSAIDs have been described in which the parent NSAID is covalently linked to a dithiolethione moiety (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) which release hydrogen sulfide. HS-NSAIDs have enhanced safety and efficacy compared to their traditional counterparts. Since NSAIDs are regarded as prototypical chempreventive agents, here we compared naproxen and its hydrogen sulfide-releasing (HS-naproxen) analog using a human colon cancer cell line and also evaluated its effect on NF-κB whose induction is strongly implicated in some cancers. Methods: HS-naproxen was synthesized and purified at our lab with 1H-NMR verification. Cell line: HT-29 human adenocarcimoma; Cell growth: MTT; Cell cycle phase distribution: Flow cytometry; Apoptosis: subdiploid (sub-G/G1) peak in DNA content histograms; Proliferation: PCNA; NF-κB: enzyme-linked immunosorbent assay (ELISA). GSH levels: colorimetric method. Results: HS-naproxen inhibited the growth of HT-29 cells with an IC50 of 72 ± 5 µM whereas for naproxen the IC50 was 2800 ± 190 µM at 24h. HS-naproxen treatment of HT-29 cells at 0.5xIC50, 1xIC50, and 2xIC50 for 24 hrs induced apoptosis (12 ± 1%, 54 ± 3%, 71 ± 3%), inhibited proliferation (PCNA, 71 ± 3%, 49 ± 5%, 26 ± 4%), and caused a G/G1 cell cycle block. Activation of NF-κB was inhibited as demonstrated by ELISA, at 0.5xIC50, 1xIC50, and 2xIC50 the reduction was 22 ± 3%, 47 ± 2%, and 62 ± 4% respectively. Cellular GSH levels were also reduced dose-dependently by HS-naproxen, suggesting a condition of oxidative stress. Conclusions: HS-naproxen inhibits HT-29 cell growth and inhibits NF-κB activation. These data suggest that HS-naproxen may be useful as chemopreventive agent against colon cancer and merits further evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2011-1353