Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets.
Rapamycin (sirolimus) is a macrolide fungicide with immunosuppressant properties that is used in human islet transplantation. Little is known about the effects of rapamycin on MIN-6 cells and islets. Rapamycin had a dose-dependent, time-dependent, and glucose-independent deleterious effect on MIN-6 cell viability. At day 1, using the MTT method, 0.01 nmol/l rapamycin reduced cell viability to 83 +/- 6% of control (P < 0.05). Using the calcein AM method, at day 2, 10 nmol/l rapamycin caused a reduction in cell viability to 73 +/- 5% of control (P < 0.001). Furthermore, 10 and 100 nmol/l rapamycin caused apoptosis in MIN-6 cells as assessed by the transferase-mediated dUTP nick-end labeling assay. Compared with control, there was a 3.1 +/- 0.6-fold increase (P < 0.01) in apoptosis in MIN-6 cells treated with 10 nmol/l rapamycin. A supra-therapeutic rapamycin concentration of 100 nmol/l significantly impaired glucose- and carbachol-stimulated insulin secretion in rat islets and had a deleterious effect on the viability of rat and human islets, causing apoptosis of both alpha- and beta-cells.
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-4399, USA.
Ewan
E
Bell
Xiaopei
X
Cao
Jacob A
JA
Moibi
Scott R
SR
Greene
Robert
R
Young
Matteo
M
Trucco
Zhiyong
Z
Gao
Franz M
FM
Matschinsky
Shaoping
S
Deng
James F
JF
Markman
Ali
A
Naji
Bryan A
BA
Wolf
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007700:Kinetics; D051379:Mice; D051381:Rats; D020123:Sirolimus / Q000633:toxicity*
D007166:Immunosuppressive Agents; D007328:Insulin; D002217:Carbachol; D005947:Glucose; D020123:Sirolimus