Blocking late cholesterol biosynthesis inhibits the growth of transplanted Morris hepatomas (7288CTC) in rats

✍ Scribed by G Xu; G Salen; M Lea; G S Tint; L B Nguyen; A K Batta; T S Chen; S Shefer

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 244 KB
• Volume: 24
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510240224

✦ Synopsis

cholesterol levels. Thus, inhibiting late cholesterol syn-The conversion of 7-dehydrocholesterol to cholesterol thesis hinders growth of rapidly enlarging malignant is the last reaction in the cholesterol biosynthesis pathtumors. (HEPATOLOGY 1996;24:440-445.) way catalyzed by the microsomal enzyme, 7-dehydrocholesterol-D 7 -reductase. We studied whether malignant tumor growth that depends on cholesterol could be Cholesterol is an essential component for all mammalian slowed by inhibiting late cholesterol biosynthesis. The cells. In combination with phospholipids, it gives structure inhibitor 7-dehydrocholester-D 7 -reductase, BM 15.766 for cell shape and when incorporated in subcellular memalone, or in combination with 2% cholesterol was fed to branes (microsomes and mitochondria) provides a surface for 20 male Buffalo rats for 2 weeks immediately after Morthe attachment of protein enzymes. Without cholesterol, ris hepatoma 7288CTC was implanted in both flanks. Tumammalian cells can not survive and fibroblasts from pamor weights were compared and sterol composition, hetients with the inborn error of cholesterol biosynthesis, patic hydroxymethyl glutaryl coenzyme A (HMG-CoA) Smith-Lemli-Opitz syndrome, grow slowly in cholesterol defireductase activity, and low-density lipoprotein (LDL) recient medium. 1 ceptor binding in the tumor were correlated with those

The Morris hepatoma 7288CTC is an extensively studied in the liver. In the plasma of rats treated with BM 15.766, rat liver tumor that grows very rapidly when transplanted cholesterol levels dropped 75% and the precursor, 7-dein the flanks of Buffalo rats. 2 A number of years ago, Sihydrocholesterol rose substantially. Tumor weights perstein and colleagues suggested that implanted Morris were 43% less (P õ .05) than controls (5.9 { 1.5 g vs. 10.4 hepatomas continued to produce cholesterol even when fed { 2.2 g) with sterol concentrations reduced 25%, and the large amounts in the diet that inhibited endogenous hepatic precursor, 7-dehydrocholesterol, increased to represent cholesterol synthesis. [3][4][5][6] They hypothesized that Morris hepa-71% of the tumor sterols. Feeding cholesterol with BM tomas might not take up cholesterol like normal liver, and 15.766 normalized plasma but only partially restored tutherefore, tumor hepatic hydroxymethyl glutaryl coenzyme mor cholesterol concentrations, which still remained A (HMG-CoA) reductase would not be down-regulated. 4 49% below the hepatomas in the control group. With BM Recently, we have discovered that homozygotes with the 15.766, hepatic cholesterol decreased 76% and was asso-Smith-Lemli-Opitz syndrome do not produce cholesterol norciated with a marked rise of 7-dehydrocholesterol that mally because of an inherited block in the last step of the could be almost entirely prevented by feeding cholescholesterol biosynthetic pathway 7 as illustrated in Fig. 1. The terol. After the tumor was implanted, hepatic HMG-CoA abnormal reaction in the Smith-Lemli-Opitz syndrome inreductase activity increased 56% and was 8.6 times volves incomplete reduction of the double bond at C-7 in higher than in the tumor. Enzyme activities were en-7-dehydrocholesterol (5,7-cholestadien-3b-ol) that forms hanced about 50% in the liver and the tumor after BM cholesterol and is catalyzed by the microsomal enzyme, 7-15.766 was administered but decreased 38% below condehydrocholesterol-D 7 -reductase. As a result of defective biotrol when cholesterol was added to the diet. Hepatic resynthesis, little cholesterol is formed and the precursor, 7ceptor-mediated LDL binding rose 67% after tumor imdehydrocholesterol, and its isomer, 8-dehydrocholesterol plantation, and declined to control levels with (5,8,9-cholestadien-3b-ol) accumulate in plasma and tissues. 8 cholesterol feeding. These results suggest that de novo Further, our results suggested that desmosterol is not on the cholesterol synthesis in Morris hepatoma 7288CTC is major pathway for cholesterol biosynthesis because neither much lower than the liver and tumor growth depends on desmosterol nor its 7-dehydro precursor, 5,7,24-cholestacirculating plasma cholesterol. Inhibiting the last step in trien-3b-ol accumulate in the homozygotes with the Smithcholesterol biosynthesis profoundly reduced tissue and Lemli-Opitz syndrome (data not published). Therefore, after plasma cholesterol concentrations and accumulated lanosterol, the alternative pathway via desmosterol is minor. precursors substantially to slow hepatoma growth.

Many developmental anomalies including facial dysmorph-Feeding cholesterol restored liver but not hepatoma ism, congenital heart defects, syndactyly of the 2nd and 3rd toes, postaxial polydactyly, and severe mental retardation with failure to thrive are seen in the Smith-Lemli-Opitz syndrome. 9,10 Moreover, homozygotes with the most serious clini-Abbreviations: HMG-CoA, hepatic hydroxymethyl glutaryl coenzyme A; LDL, low-density lipoprotein. cal phenotype show the most severe biochemical abnormali-From the Gastrointestinal Research Lab, VA Medical Center, East Orange, NJ and ties with the lowest levels of tissue and plasma cholesterol