Hyperexpression of low-density lipoprotein receptors and hydroxy-methylglutaryl-coenzyme A-reductase in human pinguecula and primary Pterygium

PURPOSE: There is now increasing evidence that pterygium and pinguecula are tumorlike tissues and that cell growth and DNA replication are closely linked to cholesterol metabolism. In this study, the expression of two main genes correlated to cholesterol metabolism--namely, the low-density lipoprotein receptor (LDL-R) gene and the hydroxy-methylglutaryl-coenzyme A-reductase (HMG-CoA-R) gene--were investigated in primary pterygium, pinguecula, and normal conjunctiva. METHODS: Pterygium, pinguecula, and normal conjunctiva samples were obtained from 30 eyes (50% men) at the time of surgery. Total RNA extracted from the specimens was subjected to semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Equal amounts of total RNA were reverse transcribed into cDNA. The cDNA was subsequently amplified by the PCR in the presence of specific primers for low-density lipoprotein receptor (LDL-R) and for hydroxy-methylglutaryl coenzyme A reductase (HMG-CoA-R). RESULTS: Semiquantitative RT-PCR analysis revealed that the mRNA levels of LDL-R and HMG-CoA-R were increased in pterygia, compared with levels in both pingueculae and normal conjunctivae. Differences were statistically significant (P <0.05), including pingueculae versus normal conjunctivae. CONCLUSIONS: This study indicates that pterygium and pinguecula have an altered metabolism of cholesterol-namely increased LDL-R and HMG-CoA-R mRNAs-as is characteristic of tumorlike tissues, and that the high expression of LDL receptors renders them amenable to be treated by photodynamic therapy with intravenously injected verteporfin

FENRETINIDE IS ACTIVE IN OSTEOSARCOMA IN VITRO BY INHIBITION OF CHOLESTEROL ESTERIFICATION

Osteosarcoma remains the most common primary malignant bone cancer affecting children and adolescents. Although the combination of systemic chemotherapy and surgery enables long-term survival in most cases, the poor prognosis of patients with metastatic or recurrent disease and the lack of establishment of second-line chemotherapy suggest that novel therapeutic strategies for this tumor are needed. Here we show that fenretinide, a synthetic derivative of all-trans-retinoic acid, is active against osteosarcoma in vitro, at concentrations identical or lower to those detectable in breast cancer patients plasma during chemopreventive clinical trials. Cell lines were HOS and MG63, known to be resistant to methotrexate and cyclophosphamide, drugs in use in osteosarcoma treatment. We demonstrate for the first time that the molecular basis of fenretinide activity is the inhibition of cholesterol esterification, with down-regulation of ACAT and MDR1 mRNA, followed by downregulation of caveolin-1 protein expression. This result is in line with our recent results obtained in VSMC and in leukemia cells. The confirm and extention of these data to different human tumors will provide evidence of a novel mechanism of either cancer or human vascular proliferation disease control by the inhibition of cholesterol esterification