Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors.

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.

• Authors: Anya Alayev, Rachel S Salamon, Yang Sun, Naomi S Schwartz, Chenggang Li, Jane J Yu, Marina K Holz
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 53 Issue 5 Pg. 637-46 (Nov 2015) ISSN: 1535-4989 [Electronic] United States
• PMID: 25844891 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Multiprotein Complexes
• Phosphoinositide-3 Kinase Inhibitors
• Stilbenes
• TSC2 protein, human
• Tsc2 protein, mouse
• Tsc2 protein, rat
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Resveratrol
• Sirolimus

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Drug Therapy, Combination
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphangioleiomyomatosis (drug therapy, genetics, immunology, pathology)
• Mechanistic Target of Rapamycin Complex 1
• Mice, SCID
• Multiprotein Complexes (antagonists & inhibitors, genetics, immunology)
• Phosphatidylinositol 3-Kinases (genetics, immunology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, immunology)
• Rats
• Resveratrol
• Signal Transduction
• Sirolimus (pharmacology)
• Stilbenes (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, immunology)
• Treatment Outcome
• Tuberous Sclerosis Complex 1 Protein
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (antagonists & inhibitors, deficiency, genetics, immunology)
• Uterine Neoplasms (drug therapy, genetics, immunology, pathology)
• Xenograft Model Antitumor Assays