Bladder cancer is the fifth most prevalent cancer;primary/second-hand tobacco exposure is the major etiologic factor. ~80% of patients present with superficial disease confined to the mucosa. Recurrence is common with invasion into muscle or even distant metastasis with fatal consequences. Bladder cancer progression involves activation of specific oncogenes and growth factors/chemokines such as CXCL-1 and/or inactivation of tumor suppressor genes (p53, retinoblastoma, BIM, p21, RASSF1A, RUNX3, and p16INK4) through mutations or epigenetic mechanisms. Epigenetic mechanism of gene silencing is dominant during tobacco carcinogen mediated bladder cancer progression;at least 50 genes are reported to undergo epigenetic modification. This mechanism of gene silencing involves specific post-translational modifications of histones, particularly histones H3 and H4. Increased histone H3 K9 and K27 trimethylation and loss of histone H4 K20 trimethylation are common abnormalities in cancers. Therefore, drugs that can reverse cancer-enriched histone modifications should be effective in not only treating invasive bladder cancer but also in preventing progression from superficial to invasive lesion. We have developed a compound called LC-1, which inhibits bladder cancer cell growth both in vivo and in vitro. This drug was originally developed as an inhibitor of the transcription factor NF-?B and it inhibited NF-?B-dependent expression of CXCL-1 in bladder cancer cells. Additionally, LC-1 reduced the levels of """"""""bad"""""""" epigenetic regulators such as polycomb protein EZH2, histone deacetylase HADC1, and CtBP-1. Furthermore, it reduced the levels of histone H3 K9 and K27 trimethylation but increased the levels of histone H4 K20 trimethylation. These LC-1 induced histone modifications correlated with reduced expression of the histone H3 K9 trimethylase SUV39h1 and increased expression of tumor suppressors RUNX3, BIM, and p21 in LC-1 treated cells. Hypothesis: LC-1 is a unique drug that can prevent bladder cancer progression by inhibiting NF-?B as well as reversing cancer-associated epigenetic changes.
Specific aim : Investigate the chemopreventive activity of LC-1 in tobacco carcinogen-induced bladder cancer in established ICR mice and Wister rat models and relate chemopreventive activity with the expression levels of p21, BIM (LC-1 inducible), EZH2, VEGF, and SUV39h1 (LC-1 repressed). Significance: Our study has immediate translational potential because LC-1 has already gone through several toxicity and pharmacokinetic studies and is currently in phase I clinical trial for leukemia. A successful leukemia trial can be translated immediately to bladder cancer chemoprevention trial for patients with superficial bladder lesions.
| Nakshatri, H; Appaiah, H N; Anjanappa, M et al. (2015) NF-?B-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT. Cell Death Dis 6:e1608 |
