dehydroxymethylepoxyquinomicin and Adenocarcinoma

Although nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)-Akt-mTOR comprise key pathways, their interrelationship in lung cancer cell survival is poorly understood and needs further analyses.. We examined the activation of the NF-κB and Akt-mTORC1-p70 S6 kinase (S6K) pathways and the effect of inhibitors for NF-κB, mTORC1, and Akt using fresh lung adenocarcinoma cells.. The cases used for this study showed constitutive NF-κB activity; however, all cases but one showed resistance to NF-κB inhibition. Further examination revealed that the resistant cases were also active in the Akt-mTORC1-S6K pathway. These cases were insensitive to mTORC1 inhibition but sensitive to Akt inhibition. Akt inhibition recovered sensitivity to NF-κB inhibition and dual inhibition showed a synergistic effect on apoptosis induction.. These results indicate that the activation of Akt involves resistance to NF-κB inhibition and both pathways synergistically support the survival of lung adenocarcinoma cells. The results also indicate that inhibition of the mTORC1-S6K pathway does not inhibit the survival of these cells.

Topics: Adenocarcinoma; Aged; Apoptosis; Benzamides; Cell Survival; Cells, Cultured; Cyclohexanones; Drug Synergism; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Multiprotein Complexes; Neoplasm Staging; NF-kappa B; Oncogene Protein v-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Tetrazoles; TOR Serine-Threonine Kinases

Activation of nuclear factor-κB (NF-κB) has been implicated in metastasis of pancreatic cancer. We investigated the effects of the novel NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) on the inhibition of liver metastasis of pancreatic cancer in a mouse model of clinical liver metastasis. Nude mice were xenografted by intra-portal-vein injection with the human pancreatic adenocarcinomas cell line AsPC-1 via small laparotomy. Mice were treated with DHMEQ and gemcitabine (GEM), alone or in combination. The combination of GEM + DHMEQ showed a stronger antitumor effect than either monotherapy. Apoptosis induction in the metastatic foci was greatest in the DHMEQ + GEM group. Significant reductions in the numbers of neovessels were also seen in the DHMEQ and/or GEM groups. Cell growth inhibition assays revealed no synergistic effect of combination therapy, although each monotherapy had an individual cytotoxic effect. Combination therapy produced the greatest inhibition of tumor cell invasiveness in chemoinvasion assay. In addition, combination therapy significantly down-regulated the expression level of matrix metalloproteinase (MMP)-9 mRNA in AsPC-1 cells. DHMEQ also markedly down-regulated interleukin-8 and MMP-9, while GEM caused moderate down-regulation of vascular endothelial growth factor in metastatic foci, demonstrated by quantitative reverse transcription-polymerase chain reaction. These results demonstrate that DHMEQ can exert anti-tumor effects by inhibiting angiogenesis and tumor cell invasion, and by inducing apoptosis. Combination therapy with DHMEQ and GEM also showed potential efficacy. DHMEQ is a promising drug for the treatment of advanced pancreatic cancer.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Blotting, Western; Cell Movement; Cell Proliferation; Cyclohexanones; Deoxycytidine; Disease Models, Animal; Fluorescent Antibody Technique; Gemcitabine; Humans; Immunoenzyme Techniques; Interleukin-8; Liver Neoplasms; Matrix Metalloproteinase 9; Mice; Mice, Nude; NF-kappa B; Pancreatic Neoplasms; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured