Hepatocellular carcinoma (HCC) is a common malignancy and often resistant to chemotherapy. Many chemotherapy regimens have been tried to control advanced HCC, but have produced a low response rate and no clear impact. CPT-11, a derivative of camptothecin, works as type-I DNA topoisomerase inhibitor and showed a major objective response rate in patients with metastatic colorectal cancer. In this study, the mechanism underlying chemo-resistance to SN-38, an active form of CPT-11, in HCC was investigated in relation to anti-apoptotic pathways NF-κB and PI3K/Akt. Hep3B was the most resistant to SN-38 among three hepatoma cell lines. NF-κB was constitutively activated in Hep3B, and SN-38 further enhanced the nuclear translocation of NF-κB. However, inactivation of NF-κB by adenovirus expressing IκB super-repressor or MG-132, proteasome inhibitor, did not sensitize Hep3B to SN-38-induced apoptosis. On the other hand, SN-38 phosphorylated Akt and pretreatment with PI3K inhibitors increased SN-38-induced apoptosis, indicating that resistance to SN-38 in Hep3B occurs partly through the PI3K/Akt not the NF-κB pathway. Blocking of PI3K/Akt may thus be helpful for overcoming chemo-resistance of HCC.

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