Abstract 6381: NBS-1120: An e-NSAID with potent anti-cancer activity targets cell cycle proteins by generating polysulfides

Abstract

Abstract Epidemiological and interventional human studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce cancer incidence and mortality. However, while NSAIDs are chemopreventive against cancer, they are not potent enough to be chemotherapeutic, and their long-term use may lead to significant gastrointestinal (GI), cardiovascular (CV) and renal side effects. In our search for a “better and safer NSAID”, we developed enhanced or e-NSAIDs. These are NSAIDs such as aspirin and naproxen, modified to release nitric oxide (NO) and hydrogen sulfide (H2S), both gaseous signaling molecules of biological relevance. NO and H2S have similar properties to prostaglandins within the GI mucosa, thus modulating the local mucosal defense systems, leading to reduced GI toxicity. Also, NO and H2S have protective roles in the CV and renal systems. NO and H2S signaling pathways regulate many mammalian physiological processes through post-translational cysteine persulfidation or nitrosylation. NO and H2S have a rich in vivo chemistry in which the molecules are transformed into short lived, bioactive species. They also react together to form highly bioactive persulfides. While both gasotransmitters have a complex role in tumor biology, their downstream effects have a profound impact on tumor growth and metastasis. e-NSAIDs and NBS-1120 in particular, have potent anti-tumor activity, demonstrated in in vivo models of colorectal, breast and pancreatic cancer. The activity of NBS-1120 is superior to the parent aspirin, NO releasing aspirin or H2S releasing aspirin. NBS-1120 has displayed the unexpected property of synergism: the sum of the parts (Aspirin+NO+H2S) does not equal the whole (NBS-1120). Here we report that NBS-1120 inhibits FOXM1, an important protein that plays a critical role in the cell cycle, is closely linked to p53 and controls the expression of cell cycle regulatory proteins. FOXM1's association with many solid tumors, its interactions with numerous signaling pathways, and its emerging role as a master regulator of DNA damage response and genotoxic agent resistance make it an important target for anticancer therapies. We describe the effects of NBS-1120 on p53, β-catenin, oxidative stress, NF-ΚB and COX1/2 through inhibition of FOXM1 by protein persulfidation and nitrosylation. Further, we report that the unique activity of e-NSAIDs is related to the simultaneous release of NO and H2S and their subsequent rapid reaction to form the highly bioactive polysulfides H2S2 and H2S3. NBS-1120 induced rapid polysulfide formation, however no evolution of H2S was detected. These data suggest that release of NO and H2S from NBS-1120 results in a very rapid reaction to form polysulfides. Mechanistically, the rapid formation of polysulfides may account for the potent activity of NBS-1120 compared to NSAIDs that release either NO or H2S alone. Citation Format: Jan J. Scicinski, Kenneth Olsen, Janet Stephens, Khosrow Kashfi. NBS-1120: An e-NSAID with potent anti-cancer activity targets cell cycle proteins by generating polysulfides [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6381.