Repressions of actin assembly and RhoA localization are involved in inhibition of tumor cell motility by lipophilic ascorbyl phosphate

Liu, Jianwen; Kayasuga, Atsushi; Nagao, Norio; Masatsuji-Kato, Eiko; Tuzuki, Toshi; Miwa, Nobuhiko

doi:10.3892/ijo.23.6.1561

Cited by 8 publications

(12 citation statements)

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“…The molecular mechanism of ascorbic acid activity with regard to the inhibition of cancer cell migration is not understood, and due to the broad biological activity of vitamin C, it is difficult to draw conclusions about the specific regulatory pathways involved in the inhibition of cell migration. It was suggested that a decrease in the intracellular ROS level induced by ascorbic acid derivatives may play an important role in the inhibition of migration, probably by interfering with redox-regulated signaling pathways [6,8,14]. However, our results indicate that the antioxidant effect of ascorbic acid is not by itself sufficient to inhibit cell migration.…”

Section: Resultscontrasting

confidence: 55%

“…This discrepancy might have resulted from the different cell lines used in the experiments. As it was demonstrated that different cell types show different sensitivities to ascorbic acid [25], it is possible that WC 256 cells are more sensitive to this compound than the cell lines used in the previous experiments [6,8,14]. Moreover, we also cannot exclude that in our model, ascorbic acid derivatives would induce inhibition of WC 256 cell migration at a lower concentration than intact vitamin C. However, our data does demonstrate that unmodified ascorbic acid may also be an efficient inhibitor of cancer cell migration.…”

Section: Resultsmentioning

confidence: 99%

“…It was also shown that ascorbic acid protects against DNA damage induced by hydrogen peroxide in human lymphocytes [13]. Moreover, it was demonstrated that the levels of hydroxyl radicals in cells treated with ascorbic acid derivatives were markedly diminished relative to those of non-treated cells as evaluated by the electron spin resonance method using the spin trapping agent DMPO [14]. The attenuation of intracellular reactive oxygen species by derivatives of vitamin C was also shown with the redox indicator CDCFH-DA [6].…”

Section: Introductionmentioning

confidence: 89%

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Ascorbic acid inhibits the migration of walker 256 carcinosarcoma cells

Wybieralska

Koza

Sroka

et al. 2008

Cellular and Molecular Biology Letters

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Abstract:The results of several experimental studies have shown that ascorbic acid inhibits tumor growth and metastasis. Ascorbic acid is an antioxidant that acts as a scavenger for a wide range of reactive oxygen species (ROS). Both tumour metastasis and cell migration have been correlated with the intracellular ROS level, so it was postulated that the inhibitory effect of ascorbic acid derivatives on cell motility may be caused by scavenging of ROS. Time-lapse analyses of Walker 256 carcinosarcoma cell migration showed that both the speed of movement and the cell displacement were inhibited by ascorbic acid applied in concentrations ranging from 10 to 250 μM. This effect correlated with a reduction in the intracellular ROS level in WC 256 cells, suggesting that ROS scavenging may be a mechanism responsible for the inhibition of WC 256 cell migration. However, another potent antioxidant, N-acetyl-L-cysteine, also efficiently decreased the intracellular ROS level in WC 256 cells, but did not affect the migration of the investigated cells. These results demonstrate that intact, unmodified ascorbic acid applied in physiologically relevant and nontoxic concentrations exerts an inhibitory effect on the migration of WC 256 carcinosarcoma cells, and that this may be one of the factors responsible for the anti-metastatic activity of vitamin C. However, our data does not support the hypothesis that the scavenging of intracellular ROS is the main mechanism in the inhibition of cancer cell migration by ascorbic acid.

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Section: Resultscontrasting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

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Ascorbic acid inhibits the migration of walker 256 carcinosarcoma cells

Wybieralska

Koza

Sroka

et al. 2008

Cellular and Molecular Biology Letters

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“…To enhance the antitumor activity of Asc, the administration of some transition metal ions with Asc (Stich et al 1979; or diverse derivatives of Asc (Hacker et al 1985;) have been studied. We have studied lipophilic derivatives of Asc including 2-ophosphoryl-6-o-palmitoyl-L-ascorbic acid (Asc2P6-Palm) and found that Asc2P6Palm was advantageous over Asc in terms of anti-metastatic activity (Liu et al 2000(Liu et al , 2003 in addition to antitumor effects Miwa et al 1988). Hyperthermia is the oldest documented tumor treatment modality (Pajonk et al 2005), and is applied in combination with chemotherapy and/or radiotherapy in the clinical setting (Takahashi et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Anticancer effects of 6-o-palmitoyl-ascorbate combined with a capacitive-resistive electric transfer hyperthermic apparatus as compared with ascorbate in relation to ascorbyl radical generation

et al. 2011

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The aim of the present study is to determine the anti-proliferative activity of 6-o-palmitoyl-L-ascorbic acid (Asc6Palm) that is a lipophilic derivative of L-ascorbic acid (Asc), on human tongue squamous carcinoma HSC-4 cells by combined use of hyperthermia in comparison to Asc. Asc6Palm or Asc were administered to HSC-4 cells for 1 h, to which hyperthermia at 42°C was applied for initial 15 min. After further 1-72 h incubation at 37°C, cell proliferation was determined with Crystal Violet staining. Ascorbyl radical (AscR) in HSC-4 cell suspension was measured by electron spin resonance (ESR), and cell morphology was observed with scanning electron microscopy (SEM). At 37°C, 4 mM Asc or 0.35 mM Asc6Palm were enough to suppress proliferation of HSC-4 cells. By combined use of hyperthermia at 42°C, cell proliferation was decreased when compared to 37°C. After Asc of 4 mM was incubated with HSC-4 cell suspensions at 37°C or 42°C for 0-180 min, the signal intensity of ascorbyl radical (AscR) by ESR was not different regardless of the presence or absence of cells at 37°C, whereas AscR signal was enlarged in the presence of HSC-4 cells at 42°C. It was suggested that oxidation of Asc occurred rapidly in HSC-4 cells by hyperthermia, and thereby enhanced the anti-proliferative activity. By SEM observation, the surface of HSC-4 cells treated with Asc6Palm revealed distinct morphological changes. Thus, the combined regimen of Asc6Palm and hyperthermia is expected to exert a marked antitumor activity.

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“…APPS has also been demonstrated to inhibit invasion of human fibrosarcoma cells (HT-1080) through the constituted basement membrane Matrigel and metastasis of mouse melanoma cells (B16-BL6) transplanted from the tail vein in mice (20).…”

Section: Discussionmentioning

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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Repressions of actin assembly and RhoA localization are involved in inhibition of tumor cell motility by lipophilic ascorbyl phosphate

Cited by 8 publications

References 0 publications

Ascorbic acid inhibits the migration of walker 256 carcinosarcoma cells

Ascorbic acid inhibits the migration of walker 256 carcinosarcoma cells

Anticancer effects of 6-o-palmitoyl-ascorbate combined with a capacitive-resistive electric transfer hyperthermic apparatus as compared with ascorbate in relation to ascorbyl radical generation

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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