Modulation of cholesterol homeostasis by antiproliferative drugs in human pterygium fibroblasts.
OBJECTIVE
The authors have previously shown that the growth of cultured fibroblasts obtained from primary pterygia was associated with an increase in cholesterol esterification, suggesting that alterations of cholesterol homeostasis may be involved in the development and progression of this disorder. This investigation was conducted to determine whether antiproliferative agents such as pioglitazone (PIO) and everolimus (EVE) may inhibit proteins involved in the cholesterol ester cycle and the proliferation of pterygium fibroblasts (PF).


METHODS
Quiescent normal conjunctival fibroblasts and PFs were treated with or without inhibitors of cell proliferation (PIO and EVE) or with inhibitors of cholesterol esterification-progesterone (Pg) and Sandoz compound (SaH)-and then were stimulated to growth by 10% fetal calf serum (FCS). Cell proliferation was assessed by counting cells. Trypan blue uptake was used to determine cell viability. mRNA and protein levels were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively.


RESULTS
PIO and EVE significantly abolished the increase in cholesterol esters, acyl-coenzyme A cholesterol acyltransferase (ACAT1), and multidrug resistance protein (MDR1) mRNA observed in growing cells. Each inhibitor upregulated ATP-binding cassette-A1 (ABCA1), neutral cholesterol ester hydrolase (NCEH) mRNA, and caveolin-1 expression in a manner similar to that of specific inhibitors of cholesterol esterification such as Pg and SaH.


CONCLUSIONS
Intracellular modifications of cholesterol homeostasis may be relevant to pterygium development. Moreover, antiproliferative agents such as PIO and EVE may represent a potential topical medication in the prevention and inhibition of pterygium growth at an early stage, probably by modulation of cholesterol ester metabolism.
Peiretti
Enrico
E
Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy.
Dessì
Sandra
S
Mulas
Claudia
C
Abete
Claudia
C
Norfo
Claudia
C
Putzolu
Marirosa
M
Fossarello
Maurizio
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000577:Amides / Q000494:pharmacology; D051242:Caveolin 1 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068338:Everolimus; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D017646:Organosilicon Compounds / Q000494:pharmacology; D000077205:Pioglitazone; D011374:Progesterone / Q000494:pharmacology; D011625:Pterygium / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D051242:Caveolin 1; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D017646:Organosilicon Compounds; D012333:RNA, Messenger; D045162:Thiazolidinediones; D011374:Progesterone; C040256:SAN 58035; D002784:Cholesterol; D000068338:Everolimus; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1; D020123:Sirolimus; D000077205:Pioglitazone