Nitric oxide (NO) donors have been shown to activate or inhibit constitutively-activated survival/anti-apoptotic pathways, such as NF-κB, in
cancer cells. We report here that treatment of
drug-resistant human prostate
carcinoma cell lines with high levels (500-1000 μM) of the NO-donor
DETANONOate sensitized the resistant
tumor cells to apoptosis by CDDP and the combination was synergistic. We hypothesized that
DETANONOate inhibits previously identified NF-κB-regulated resistant factors such as Yin Yang 1 (YY1) and Bcl-2/BclXL. Lysates from
tumor cells treated with
DETANONOate showed inhibition of YY1 and BclXL expressions. Transfection with either YY1 or BclXL
siRNA resulted in the inhibition of both YY1 and BclXL expressions and sensitized the cells to CDDP apoptosis. Mice bearing PC-3
tumor xenografts and treated with the combination of
DETANONOate and CDDP resulted in significant inhibition of
tumor growth; treatment with single agent alone did not have any effect on
tumor growth. Analysis of patients TMA tissues with
prostatic cancer revealed higher expression of both YY1 and BclXL as a function of
tumor grades and their levels were directly correlated. Thus, both YY1 and BclXL are potential prognostic
biomarkers. Overall, the above findings suggest that one mechanism of
DETANONOate-induced sensitization of resistant
tumor cells to CDDP correlated with the inhibition of NF-κB and its targets YY1 and BclXL. The examination of the combination of NO donors and cytotoxic
therapy in the treatment of resistant
prostate cancer may be warranted.