Blocking of PI3K/Akt pathway enhances apoptosis induced by SN-38, an active form of CPT-11, in human hepatoma cells.
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-kappaB and PI3K/Akt. Hep3B was the most resistant to SN-38 among three hepatoma cell lines. NF-kappaB was constitutively activated in Hep3B, and SN-38 further enhanced the nuclear translocation of NF-kappaB. However, inactivation of NF-kappaB by adenovirus expressing IkappaB 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-kappaB pathway. Blocking of PI3K/Akt may thus be helpful for overcoming chemo-resistance of HCC.
Koizumi
Naoki
N
Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Hatano
Etsuro
E
Nitta
Takashi
T
Tada
Masaharu
M
Harada
Nobuko
N
Taura
Kojiro
K
Ikai
Iwao
I
Shimahara
Yasuyuki
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D000077146:Irinotecan; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human