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-kappaB 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-kappaB, 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-kappaB and attenuated NF-kappaB 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 microg/ml), c-IAP-1 mRNA levels. At 10 microg/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-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.
Poma
Paola
P
Dipartimento di Scienze Farmacologiche, Università di Palermo, I-90127 Palermo, Italy.
Notarbartolo
Monica
M
Labbozzetta
Manuela
M
Sanguedolce
Rosario
R
Alaimo
Alessandra
A
Carina
Valeria
V
Maurici
Annamaria
A
Cusimano
Antonella
A
Cervello
Melchiorre
M
D'Alessandro
Natale
N
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003512:Cyclohexanones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D051020:bcl-X Protein / Q000235:genetics
D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; C496800:NAIP protein, human; D016328:NF-kappa B; D051616:Neuronal Apoptosis-Inhibitory Protein; D012333:RNA, Messenger; D051020:bcl-X Protein; C464444:dehydroxymethylepoxyquinomicin; D002945:Cisplatin