The biochemical mechanism of selective heat sensitivity of cancer cells

Mondovı̀, Bruno; A, Finazzi Agrò; Rotilio, Giuseppe; Strom, Roberto; Moricca, G; A, Rossi Fanelli

doi:10.1016/0014-2964(69)90060-7

Cited by 134 publications

(41 citation statements)

References 17 publications

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“…The human melanoma FME cell line used in the present work, showed somewhat less inhibition of protein synthesis than the more heat sensitive Chinese hamster ovary (CHO) cells (Henle & Leeper, 1979;Hahn & Shiu, 1985) and Novikoff hepatoma cells (Mondovi et al, 1969). The recovery of protein synthesis started immediately after heating, while CHO cells showed a delay in the recovery of 2-4h.…”

Section: Discussionmentioning

confidence: 62%

“…Hyperthermia induces a wide range of biochemical changes in mammalian cells, of which inhibition of protein synthesis is one of the most rapid and pronounced effects (McCormick & Penman, 1969;Mondovi et al, 1969;Giovanella et al, 1970;Dickson & Shah, 1972;Fuhr, 1974;Bleiberg & Sohar, 1975;Henle & Leeper, 1979). It has been suggested that the plasma membrane is a primary target for heat inactivation of cells (Szmigielski & Janiak, 1978;Wallach, 1978;Dewey et al, 1980;Tompkins et al, 1981), and that the irreversible changes in the membrane after hyperthermia are most likely due to protein damage (Westra & Dewey, 1971;Dewey et al, 1977;Lepock, 1982;Lepock et al, 1982).…”

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confidence: 99%

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Relationship between changes in antigen expression and protein synthesis in human melanoma cells after hyperthermia and photodynamic treatment

Cl¹,

Ranheim²,

Malik³

et al. 1988

Br J Cancer

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Summary Hyperthermia and photoactivated hematoporphyrin derivative induce a dose-dependent reduction in the expression of the p250 surface melanoma-associated antigen on the human FME cell line. Expression of this glycoprotein antigen was quantitated by immunofluorescence flow cytometry based on the monoclonal antibody 9.2.27. Decrease in antigen expression was followed by a transient increase above the level for untreated cells, before normalization occurred about one week after treatment.These treatment-induced changes in antigen expression could partly be explained by changes in protein synthesis. This conclusion was based on the following observations: Hyperthermia and photoactivated hematoporphyrin derivative both inhibited protein synthesis. The latter increased again rapidly to rates above normal until antigen expression reached normal level, whereupon the protein synthesis rate decreased to normal.Inhibition of protein synthesis by cycloheximide 1 day after heating, prevented the recovery of antigen expression, demonstrating that protein synthesis is necessary for resumption of normal antigen expression.The changes in both antigen expression and protein synthesis were dose-dependent, and the magnitude and duration of the changes increased with increasing dose. The time courses of the changes in protein synthesis after two different treatments which both inactivated two logs of cells were almost identical, as were the time courses after two lower heat doses inactivating one log of cells. These similarities were reflected in the changes in antigen expression.At the same time as protein synthesis reached its maximum and antigen expression resumed normal level, an increase in the Golgi apparatus was observed ultrastructurally, indicating an increased synthesis rate and transportation of glycoproteins to the cell surface.

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Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Relationship between changes in antigen expression and protein synthesis in human melanoma cells after hyperthermia and photodynamic treatment

Cl¹,

Ranheim²,

Malik³

et al. 1988

Br J Cancer

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“…The WT transformants were also somewhat temperature sensitive, as has occasionally been observed in other WT SV40-transformed cell populations (2,3,5,18). The molecular mechanism of the thermal sensitivity of transformed cells is a well described, but as yet poorly understood, phenomenon (19,20). Since (Fig.…”

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confidence: 57%

Simian virus 40 A gene function: DNA content analysis of Chinese hamster cells transformed by an early temperature-sensitive virus mutant.

Robinson¹,

Lehman²

1978

Proc. Natl. Acad. Sci. U.S.A.

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Replication of two Chinese hamster embryo cell lines transformed by an early temperature-sensitive mutant of simian virus 40, tsAS8, was examined by flow microfluorometry and autoradiography of [3H~thymidine-labeled cells in order to determine whether transformed cell DNA synthesis is initiated by the virus A gene. At the permissive temperature (370), cells transformed by the mutant were like the wild-type virus transformants in appearance, colony-forming ability, high saturation density, and rapid replication. At One approach to understanding neoplasia has been to study cells transformed by temperature-sensitive virus mutants at temperatures permissive and nonpermissive for the function of specific viral genes. In this way, the A gene of simian virus 40 (SV40) has been tentatively identified as the gene responsible for initiation and maintenance of transformation in mammalan cells (1-6). In the lytic system, the A gene initiates viral and perhaps cellular DNA synthesis (6-8). It has therefore been suggested that transformation of nonpermissive cells is maintained by the A gene product continuously initiating cell DNA synthesis, which would free cell replication from its normal control mechanisms (1-5, 9, 10).If this "initiator" hypothesis is correct, cells transformed by SV40 mutants that specify a temperature-sensitive A gene product (tsA mutants) should not only lose the transformed phenotype at the nonpermissive temperature, but also should return to normal growth control, and arrest in the G1 (Go) phase of the cell cycle at confluence as normal cells do. When grown at the permissive temperature, the same cells should resume cell cycle traverse in response to the functional A gene. This "initiator" hypothesis was tested by analyzing the cell cycle of Chinese hamster embryo (ChH) cells transformed by wild-type (WT) SV40 and the SV40 tsA mutant, tsA58. Several independent methods of cell cycle analysis, including flow microfluorometric determination of cell DNA content, were used. The results of our studies suggest that the loss of the A gene function represented by the tsA58 mutation does not allow SV40-transformed ChH cells to arrest in the G1 (Go) phase of the cell cycle.MATERIALS AND METHODS Viruses and Cell Cultures. WT SV40 and the temperature-sensitive group A SV40 mutant, tsA58, were obtained from Peter Tegtmeyer. Virus pools were prepared and were plaque assayed on CV-1 monkey kidney cells at 330 and 40.5°(11). The presence of SV40-induced T or V antigen in infected cells was demonstrated by indirect immunofluorescence (12).Confluent secondary cultures of normal ChH fibroblasts (12) were infected with 2-5 plaque-forming units of SV40 per cell at 370 and subcultured frequently until morphologic transformation was observed (five to six passages). This uncloned population, selected only for rapid growth on plastic, was designated ChH A58. Another embryo cell culture was similarly infected with WT or tsA58 SV40, but the cells were seeded into soft agar (13) after morphologic transformation was o...

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“…In this study, their activity was compared using human tongue squamous carcinoma cells (HSC-4). Hyperthermia, is a potent cancer treatment (9), which inhibits the growth of tumor cells (10)(11)(12) and DNA synthesis (13)(14)(15), and is in clinical use for cancer therapy. This study aimed to examine whether these derivatives of Asc increase tumor cell death caused by hyperthermia, to further improve cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Carcinostatic effects of diverse ascorbate derivatives in comparison with aliphatic chain moiety structures: Promotion by combined hyperthermia and reduced cytotoxicity to normal cells

et al. 2012

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Abstract. In this study, using human tongue squamous carcinoma cells (HSC-4) carcinostatic activity was compared for diverse L-ascorbic acid (Asc) derivatives, including the 'straight-C 16 -chain types', 6-O-palmitoyl-Asc (A6-P) and Asc-2-phosphate-6-O-palmitate sodium salt (APPS), as well as the 'branched-C 16 -chain types', Asc-2-phosphate-6-O-(2'-hexyl) d e ca noat e (A PH D), a n isom e r of A PPS, a nd Asc-2,3,5,6-O-tetra-(2'-hexyl)decanoate (VCIP). The order of magnitude of the carcinostatic effects at 37˚C was: APPS>A6-P = APHD>VCIP and at 42˚C was APPS = A6-P>APHD>VCIP. Therefore, the two straight-C 16 -chain derivatives, APPS and A6-P, had a greater effect compared to the two branched-C 16 -chain Asc derivatives, which are considered to have more difficulty with 'orientation along cell-membrane-glycerolipid direction'. APPS-treated HCS-4 cells were observed for a decrease in cell number, cell shrinkage, pycnosis indicative of apoptosis and cell deformation. The order of cytotoxicity for the normal human dermal fibroblasts (OUMS-36) at 37˚C was: A6-P (50% inhibitory concentration: 150-300 µM)>APHD (450-600 µM)>>Asc = APPS (800-1000 µM). Accordingly, APHD was more cytotoxic than APPS, since the straight-C 16 -chain type, which was eliminated after the enzymatic esterolysis of APPS, is metabolized via the 'fatty acid β-oxidation cycle' more efficiently in normal cells. Thus, APPS had a greater advantage over APHD, A6-P and VCIP in terms of carcinostatic effects at 37˚C, carcinostasis promotion at 42˚C and a decrease of cytotoxicity to normal cells. This observation suggests a marked potential for aliphatic chain-moiety structures as anticancer agents, due to their cancer-selective carcinostasis and combined efficacy with hyperthermia, without causing side effects. IntroductionAscorbic acid (Asc) and its oxidized form, dehydroascorbic acid, are important in the inhibitory control of the division and growth of cells in animal tissues (1). Asc has been reported to be a potent antitumor agent (2), but extremely high doses are required for carcinostatic effects. To increase the activity, Asc in combination with supplements (3,4) and the use of its derivatives generate hydrogen peroxide (5,6). Asc acylated with palmitic acid on the 6-O-site suppresses cell growth (7) and DNA synthesis (8). The 6-O-palmitoyl derivative of Asc has been demonstrated to exert cytotoxicity to tumor cells through hydrogen peroxide generation (6). The carcinostatic activity of diverse Asc derivatives consisting of a palmitoyl moiety and phosphatidyl moiety has been demonstrated. Their chemical structures are shown in Table Ⅰ. In this study, their activity was compared using human tongue squamous carcinoma cells (HSC-4). Hyperthermia, is a potent cancer treatment (9), which inhibits the growth of tumor cells (10-12) and DNA synthesis (13-15), and is in clinical use for cancer therapy. This study aimed to examine whether these derivatives of Asc increase tumor cell death caused by hyperthermia, to further improve cancer treatment.Tumor c...

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The biochemical mechanism of selective heat sensitivity of cancer cells

Cited by 134 publications

References 17 publications

Relationship between changes in antigen expression and protein synthesis in human melanoma cells after hyperthermia and photodynamic treatment

Relationship between changes in antigen expression and protein synthesis in human melanoma cells after hyperthermia and photodynamic treatment

Simian virus 40 A gene function: DNA content analysis of Chinese hamster cells transformed by an early temperature-sensitive virus mutant.

Carcinostatic effects of diverse ascorbate derivatives in comparison with aliphatic chain moiety structures: Promotion by combined hyperthermia and reduced cytotoxicity to normal cells

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