Antitumor effects of the novel NF-kappaB 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-kB inhibitor dehydroxymethylepoxyquinomicin
(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-?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-kB and
attenuated NF-?B activation by cisplatin. It down-regulated
Bcl-XL mRNA in a dose-dependent manner and up-regulated
that of Bcl-XS. It also decreased interleukin 6 (IL-6), NAIP
and, after 16 h of exposure to the higher concentration
tested (10 ug/ml), c-IAP-1 mRNA levels. At 10 ?g/ml it
caused significant increase in Bax, XIAP, cyclin D1 and ßcatenin
mRNAs. The combination of DHMEQ with cisplatin
produced unexpected significant decrease in c-IAP-2 and
Bcl-XS mRNAs as well as additive decrease (IL-6, NAIP
and, after 16 h, Bcl-XL) 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 DHMEQ 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.