Abstract
Aim:
We investigated the effects of TORC1/2 kinase inhibitors on colorectal cancer (CRC) cell lines.
Materials & methods:
Using selective TORC1/2 inhibitors, rapamycin and PP242, we assessed their effect on the growth of CRC cells in vitro and tumor growth in vivo.
Results:
Rapamycin and PP242 inhibit proliferation and induce apoptosis of CRC cells. They also enhance proapoptotic effect of conventional chemo drug doxorubicin in CRC cells in vitro. When combined with doxorubicin, rapamycin and PP242 almost completely inhibit tumor growth in vivo. Rapamycin and PP242 inhibit phosphorylation of Akt, ribosomal S6 kinase, 4EBP1 and mTOR.
Conclusion:
Our study suggests rapamycin and PP242 may be a useful therapeutic agent and inhibiting mTOR signaling pathway represents a new targeted therapy for CRC.
Keywords:
PP242; colorectal cancer; mTOR signaling pathway; rapamycin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colorectal Neoplasms / drug therapy
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / pathology
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Disease Models, Animal
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Doxorubicin / pharmacology
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Humans
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Indoles / pharmacology
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Multiprotein Complexes / antagonists & inhibitors*
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Protein Kinase Inhibitors / pharmacology*
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Purines / pharmacology
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Tumor Stem Cell Assay
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Indoles
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Multiprotein Complexes
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Protein Kinase Inhibitors
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Purines
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Doxorubicin
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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TOR Serine-Threonine Kinases
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PP242
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Sirolimus