osi-027 and Liver-Neoplasms

osi-027 has been researched along with Liver-Neoplasms* in 2 studies

Other Studies

2 other study(ies) available for osi-027 and Liver-Neoplasms

ArticleYear
Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells.
    Oncotarget, 2017, Feb-07, Volume: 8, Issue:6

    Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells. We showed that AT406 induced degradation of IAPs (cIAP-1 and XIAP), but didn't affect another anti-apoptosis protein Mcl-1. Co-treatment of OSI-027 caused simultaneous Mcl-1 downregulation to overcome AT406's resistance. Significantly, shRNA knockdown of Mcl-1 remarkably facilitated AT406-induced apoptosis in HCC cells. In vivo, AT406 oral administration suppressed HepG2 tumor growth in nude mice. Its activity was potentiated with co-administration of OSI-027. We conclude that mTOR could be a key resistance factor of AT406 in HCC cells.

    Topics: Acetates; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azocines; Benzhydryl Compounds; Benzopyrans; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Hep G2 Cells; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Mice, Nude; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Protein Stability; Proteolysis; Ribosomal Protein S6 Kinases, 70-kDa; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Triazines; Tumor Burden; Ubiquitin-Protein Ligases; X-Linked Inhibitor of Apoptosis Protein; Xenograft Model Antitumor Assays

2017
Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells.
    Molecular cancer therapeutics, 2015, Volume: 14, Issue:8

    mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0-G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027-induced cell-cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. Mol Cancer Ther; 14(8); 1805-15. ©2015 AACR.

    Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Imidazoles; Inhibitory Concentration 50; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Multiprotein Complexes; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Triazines; Tumor Burden; Xenograft Model Antitumor Assays

2015
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