Membrane alterations in cancer cells: the role of oxy radicals.

Membranes isolated from tumor cells present profound alterations in their composition, structural organization, and functional properties. In this study we have reported some of these alterations in microsomal and plasma membranes of hepatomas with different growth rate and degree of differentiation. The chemical parameters studied were the phospholipid-to-protein, the cholesterol-to-protein, and the cholesterol-to-phospholipid ratios and the fatty acid composition of the phospholipids. The physical parameters were the molecular order (static) and the fluidity (dynamic), determined, respectively, as the order parameter [P2] and the correlation time tau R of the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH). The functional property investigated was the ability of the membranes to undergo superoxide-induced lipid peroxidation, determined as byproduct (malondialdehyde and lipid hydroperoxides) formation and as changes in the fatty acid acyl residues. Changes in the physical state of the membrane, induced by oxy radicals, were also monitored during lipid peroxidation. A study of the antioxidant activity of the tumor cell, in terms of oxy radical enzymatic defenses (superoxide dismutase, glutathione peroxidase and catalase) was also performed. The main results obtained are the following: hepatoma membranes possess a lower phospholipid content and a lower degree of fatty acid unsaturation; on the other hand, the cholesterol-to-phospholipid ratio is increased; the physical state appears characterized by an increased rigidity (increased molecular order of the lipids and decreased fluidity); the membrane peroxidizability is markedly depressed and its order parameter, in contrast to liver membranes, does not increase with exposure to the action of O2- radicals; and the oxy radical enzymatic defense mechanisms are decreased. All these alterations increase with increasing growth rate and dedifferentiation of the tumor. Considering all of the data, we are inclined to think that tumor membranes are altered structurally and functionally in part as the result of an oxy radical-induced damage that takes place in vivo under conditions of increased oxygen toxicity.

[1]  K. Wilbur,et al.  Lipid peroxide formation in regenerating rat liver. , 1956, Experimental cell research.

[2]  A. Ottolenghi,et al.  Inhibition of cell division by ultraviolet irradiated unsaturated fatty acid. , 1957, Experimental cell research.

[3]  J. Huff,et al.  Lipide peroxide production and inhibition by tumor mitochondria. , 1960, Archives of biochemistry and biophysics.

[4]  K. Utsumi,et al.  Failure of FE2+-induced lipid peroxidation and swelling in the mitochondria isolated from ascites tumor cells. , 1965, Biochimica et biophysica acta.

[5]  H. Morris,et al.  Microbodies of Morris hepatomas. , 1971, Cancer research.

[6]  S. Aust,et al.  Evidence for superoxide generation by NADPH-cytochrome c reductase of rat liver microsomes. , 1972, Biochemical and biophysical research communications.

[7]  B Chance,et al.  The cellular production of hydrogen peroxide. , 1972, The Biochemical journal.

[8]  E. Cadenas,et al.  Mitochondrial production of superoxide anions and its relationship to the antimycin insensitive respiration , 1975, FEBS letters.

[9]  T. Galeotti,et al.  Superoxide radicals and hydrogen peroxide formation in mitochondria from normal and neoplastic tissues. , 1975, Biochimica et biophysica acta.

[10]  W. Caspary,et al.  CHAPTER 7 – The Involvement of Free Radicals in Chemical Carcinogenesis , 1977 .

[11]  R. Holmes,et al.  Peroxisomes: new aspects of cell physiology and biochemistry. , 1977, Physiological reviews.

[12]  G. Milo,et al.  Fatty acids and their prostaglandin derivatives: inhibitors of proliferation in aortic smooth muscle cells. , 1977, Science.

[13]  H. Morris,et al.  The deacylation and reacylation of phosphoglyceride in microsomes of Morris hepatoma 7777 and host rat liver. , 1977, Cancer research.

[14]  I. Zbarsky,et al.  Superoxide dismutase and glutathione peroxidase activities in tumors , 1977, FEBS letters.

[15]  T. Galeotti,et al.  Production of superoxide anions and hydrogen peroxide in Ehrlich ascites tumour cell nuclei. , 1977, Biochimica et biophysica acta.

[16]  T. Galeotti,et al.  Different contribution of rat liver microsomal pigments in the formation of superoxide anions and hydrogen peroxide during development. , 1977, Archives of biochemistry and biophysics.

[17]  D. Mills,et al.  NADPH-dependent lipid peroxidation in mitochondria from livers of young and old rats and from rat hepatoma D30 [proceedings]. , 1977, Biochemical Society transactions.

[18]  T. Galeotti,et al.  Growth-related lipid peroxidation in tumour microsomal membranes and mitochondria. , 1979, Biochimica et biophysica acta.

[19]  L. Oberley,et al.  Role of superoxide dismutase in cancer: a review. , 1979, Cancer research.

[20]  I. Zbarsky,et al.  A novel type of superoxide generating system in nuclear membranes from hepatoma 22a ascites cells , 1980, FEBS letters.

[21]  L. Oberley,et al.  Superoxide dismutase and superoxide radical in Morris hepatomas. , 1980, Cancer research.

[22]  T. Galeotti,et al.  Superoxide dismutase content and microsomal lipid composition of tumours with different growth rates. , 1980, Biochimica et biophysica acta.

[23]  E. Miller,et al.  Mechanisms of chemical carcinogenesis , 1981, Cancer.

[24]  H. Forman,et al.  CHAPTER 3 – Superoxide Radical and Hydrogen Peroxide in Mitochondria , 1982 .

[25]  S. Kawato,et al.  Microsomal lipid peroxidation causes an increase in the order of the membrane lipid domain , 1982, FEBS letters.

[26]  Weiss Sj,et al.  Phagocyte-generated oxygen metabolites and cellular injury , 1982 .

[27]  D. Cornwell,et al.  Regulation of cell division in a human glioma cell clone by arachidonic acid and alpha-tocopherolquinone. , 1982, Cancer letters.

[28]  W. S. Thayer,et al.  Differential effect of lipid peroxidation on membrane fluidity as determined by electron spin resonance probes. , 1983, Biochimica et biophysica acta.

[29]  N. Porter.  [32] Chemistry of lipid peroxidation , 1984 .

[30]  J. Farber,et al.  Lipid peroxidation increases the molecular order of microsomal membranes. , 1984, Archives of biochemistry and biophysics.

[31]  T. Galeotti,et al.  Superoxide-dependent lipid peroxidation and vitamin E content of microsomes from hepatomas with different growth rates. , 1985, Archives of biochemistry and biophysics.