Abstract
Lymphangioleiomyomatosis (LAM) is a rare neoplastic metastatic disease affecting women of childbearing age. LAM is caused by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) as a consequence of tuberous sclerosis complex (TSC) 1/2 inactivation. Clinically, LAM results in cystic lung destruction. mTORC1 inhibition using rapamycin analogs (rapalogs) is partially effective in reducing disease progression and improving lung function. However, cessation of treatment results in continued progression of the disease. In the present study, we investigated the effectiveness of the combination of rapamycin treatment with resveratrol, an autophagy inhibitor, in the TSC2-null xenograft tumor model. We determined that this combination inhibits phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K/Akt/mTORC1 signaling and activates apoptosis. Therefore, the combination of rapamycin and resveratrol may be an effective clinical strategy for treatment of LAM and other diseases with mTORC1 hyperactivation.
Keywords:
LAM; TSC2; mTORC1; rapamycin; resveratrol.
Publication types
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Research Support, N.I.H., Extramural
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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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Drug Therapy, Combination
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Lymphangioleiomyomatosis / drug therapy*
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Lymphangioleiomyomatosis / genetics
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Lymphangioleiomyomatosis / immunology
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Lymphangioleiomyomatosis / pathology
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Mechanistic Target of Rapamycin Complex 1
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Mice, SCID
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / genetics
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Multiprotein Complexes / immunology
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Rats
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Resveratrol
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Signal Transduction
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Sirolimus / pharmacology*
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Stilbenes / pharmacology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / immunology
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Treatment Outcome
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / immunology
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Uterine Neoplasms / drug therapy*
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Uterine Neoplasms / genetics
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Uterine Neoplasms / immunology
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Uterine Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Multiprotein Complexes
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Phosphoinositide-3 Kinase Inhibitors
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Stilbenes
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TSC2 protein, human
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Tsc2 protein, mouse
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Tsc2 protein, rat
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Resveratrol
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Sirolimus