Antiproliferative effect of nitrosulindac (NCX 1102), a new nitric oxide-donating non-steroidal anti-inflammatory drug, on human bladder carcinoma cell lines

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are potent antitumoral agents but their side effects limit their clinical use. A novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), was found to be safer and more active than classical NSAIDs. This study explored the effect of the NO-donating sulindac derivative, NCX 1102, on three human urothelial epithelial carcinoma cell lines (T24, 647V, and 1207) and primary cultures of normal urothelial cells. Cytotoxicity, antiproliferative effect, cell cycle alterations, morphological changes, and apoptosis were investigated after treatment with NCX 1102 in comparison with the native molecule. After treatment, there was a cytotoxic effect (with IC50 at 48 h of 23.1 μm on 647V, 19.4 μm on T24, and 14.5 μm on 1207) and an antiproliferative effect on all three cell lines with NCX 1102 but not with sulindac. No effect was detected on normal urothelial cells. Flow cytometric analysis showed a differential NCX 1102-induced accumulation of cells in various phases of the cell cycle, depending on cell line and concentration. NCX 1102 induced an occurrence of multinucleated cells in all cell lines and mitotic arrest in 647V and 1207. NCX 1102-treated T24 and 647V cell lines showed a significant difference of apoptotic cell amount when compared to controls. Our results demonstrated a greater antiproliferative potency of NCX 1102 compared to its parent molecule sulindac, and suggested that this new NO-NSAID may have therapeutic impact in the management of bladder cancer.

Understanding the Clinical Use of Levosimendan and Perspectives on its Future in Oncology

“…Numerous investigations have proven the ability of NO to prevent the proliferation of various types of cancer cells, as evidenced by studies [ 79 , 80 , 81 , 82 , 83 ]. One particularly promising substance, known as GIT-27NO, serves as a source of NO and has demonstrated the ability to prevent the growth of prostate cancer cells (PC3 and LnCap) in a dose-dependent manner, as shown in experiments performed on mice without functional immune systems [ 84 ].…”

Repurposing of the Drug Tezosentan for Cancer Therapy

“…NO can alter the expression of genes involved in DNA repair and tumor suppression, as well as affect processes such as apoptosis and metastasis [68]. Studies have shown that NO can inhibit the growth of various cancer cells, including gastric [69], breast [70], prostate [71], and bladder cancer cells [72], as well as neural precursor cells [73]. GIT-27NO, a novel NO donor, has been shown to inhibit the growth of PC3 and LnCap prostate cancer cells in a concentration-dependent manner when xenografted into nude mice [74].…”

“…The combination of NO and ionizing radiation can also induce apoptotic cell death by activating the p53 pathway. In one study, treating colorectal cancer cells with NO donors resulted in a significant increase in the radiosensitivity of the Studies have shown that NO can inhibit the growth of various cancer cells, including gastric [69], breast [70], prostate [71], and bladder cancer cells [72], as well as neural precursor cells [73]. GIT-27NO, a novel NO donor, has been shown to inhibit the growth of PC3 and LnCap prostate cancer cells in a concentration-dependent manner when xenografted into nude mice [74].…”

Nitrosative stress in cancer therapy

“…Delivery methods include nitric oxide donor drugs and iNOS gene transfer that can achieve concentrations of NO ⋅ in the micromolar range. This lead to apoptosis in a wide variety of human cancer cells including bladder (132)(133)(134) breast (135), colon (136,137), pancreas (138,68) and prostate (139). There is also some evidence that NO ⋅ mediated apoptosis may show some selectivity for transformed compared with normal cells (fibroblasts) and that this can be attributed to increased superoxide production in transformed cells leading, on interaction with NO ⋅ , to peroxynitrite production (51).…”