Antitumor effects of the novel NF-kappa B inhibitor dehydroxymethyl-epoxyquinomicin on human hepatic cancer cells: Analysis of synergy with cisplatin and of possible correlation with inhibition of pro-survival genes and IL-6 production

We tested the novel NF-kappa B inhibitor dehydroxy-methylepoxyquinomicin (DHMEQ) in the hepatic cancer (HCC) HepG2, HA22T/VGH and HuH-6 cells. The sensitivity to the cell growth inhibitory and apoptotic effects of the agent increased along with the levels of constitutively activated NF-kappa B, which were low in HepG2 and higher in HA22T/VGH and HuH-6. In HA22T/VGH, DHMEQ exhibited synergy with cisplatin. In the same cells, DHMEQ exerted dose-dependent decreases in the nuclear levels of activated NF-kappa B and attenuated NF-kappa B activation by cisplatin. It down-regulated Bcl-X-L mRNA in a dose-dependent manner and up-regulated that of Bcl-X-S. It also decreased interleukin 6 (IL-6), NAIP and, after 16 h of exposure to the higher concentration tested (10 mu g/ml), c-IAP-1 mRNA levels. At 10 mu g/ml it caused significant increase in Bax, XIAP, cyclin D1 and beta-catenin mRNAs. The combination of DHMEQ with cisplatin produced unexpected significant decrease in c-IAP-2 and Bcl-X-S mRNAs as well as additive decrease (IL-6, NAIP and, after 16 h, Bcl-X-L) or increase (XIAP at 8 h) in gene expression. HA22T/VGH produce IL-6; in agreement with the results on mRNA, DHMEQ inhibited such a process. HA22T/VGH lack the IL-6 receptor alpha chain, ruling out that in these cells the antitumor effects of DBMEQ may be attributed to an interference with a growth stimulatory autocrine loop based on IL-6. However, the use of DHMEQ in HCC might be beneficial to contrast the adverse systemic effects of the released cytokine.