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

Kato, Shinya; Asada, Ryoko; Kageyama, Katsuhiro; Saitoh, Yasukazu; Miwa, Nobuhiko

doi:10.1007/s10616-011-9363-8

Cited by 19 publications

(13 citation statements)

References 27 publications

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“…Pilot trials on patients with glioblastoma multiforme have reported that CRET treatment can reduce peritumoral edema and intratumoral vascularization, and induce extensive necrosis in the tumor core and significant tumor growth reduction, without affecting the surrounding healthy brain tissue (9). More recently, Kato et al (22) have shown that CRET treatment administered at thermal doses can significantly potentiate the anticancer effect of 6-O-palmitoyl-ascorbate on human tongue squamous carcinoma cells. Moreover, recent experimental studies by our group have shown that in vitro stimulation with subthermal doses of 0.57 MHz, CRET electric currents, induces partial cytostasis in the human hepatocarcinoma cell line HepG2 (16).…”

Section: Discussionmentioning

confidence: 99%

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells

et al. 2012

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Recently, a number of electric and electrothermal therapies have been applied to the treatment of specific cancer types. However, the cellular and molecular mechanisms involved in the response to such therapies have not been well characterized yet. Capacitive-resistive electric transfer (CRET) therapy uses electric currents at frequencies within the 0.45–0.6 MHz range to induce hyperthermia in target tissues. Preliminary trials in cancer patients have shown consistent signs that CRET could slow down growth of tumor tissues in brain gliomas, without inducing detectable damage in the surrounding healthy tissue. Previous studies by our group have shown that subthermal treatment with 0.57-MHz electric currents can induce a cytostatic, not cytotoxic response in HepG2 human hepatocarcinoma cells; such effect being mediated by cell cycle alterations. In contrast, the study of the response of NB69 human neuroblastoma cells to the same electric treatment revealed consistent indications of cytotoxic effects. The present study extends the knowledge on the response of NB69 cells to the subthermal stimulus, comparing it to that of primary cultures of human peripheral blood mononuclear cells (PBMC) exposed to the same treatment. The results showed no sensitivity of PBMC to the 0.57 MHz subthermal currents and confirmed that the treatment exerts a cytotoxic action in NB69 cells. The data also revealed a previously undetected cytostatic response of the neuroblastoma cell line. CRET currents affected NB69 cell proliferation by significantly reducing the fraction of cells in the phase G2/M of the cell cycle at 12 h of exposure. These data provide new information on the mechanisms of response to CRET therapy, and are consistent with a cytotoxic and/or cytostatic action of the electric treatment, which would affect human cells of tumor origin but not normal cells with a low proliferation rate.

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Section: Discussionmentioning

confidence: 99%

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells

et al. 2012

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“…In what concerns to CRET specifically, it has been shown to potentiate the action of antitumor agents on the human tongue squamous carcinoma HSC-4 [13]. Also, recent experimental results indicate that CRET effectiveness in cancer treatment may be enhanced by taking advantage of the ability of the radiofrequency current to heat metal nanoparticles embedded in the tumoral tissue [14].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms Underlying Antiproliferative and Differentiating Responses of Hepatocarcinoma Cells to Subthermal Electric Stimulation

2014

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Capacitive Resistive Electric Transfer (CRET) therapy applies currents of 0.4–0.6 MHz to treatment of inflammatory and musculoskeletal injuries. Previous studies have shown that intermittent exposure to CRET currents at subthermal doses exert cytotoxic or antiproliferative effects in human neuroblastoma or hepatocarcinoma cells, respectively. It has been proposed that such effects would be mediated by cell cycle arrest and by changes in the expression of cyclins and cyclin-dependent kinase inhibitors. The present work focuses on the study of the molecular mechanisms involved in CRET-induced cytostasis and investigates the possibility that the cellular response to the treatment extends to other phenomena, including induction of apoptosis and/or of changes in the differentiation stage of hepatocarcinoma cells. The obtained results show that the reported antiproliferative action of intermittent stimulation (5 m On/4 h Off) with 0.57 MHz, sine wave signal at a current density of 50 µA/mm2, could be mediated by significant increase of the apoptotic rate as well as significant changes in the expression of proteins p53 and Bcl-2. The results also revealed a significantly decreased expression of alpha-fetoprotein in the treated samples, which, together with an increased concentration of albumin released into the medium by the stimulated cells, can be interpreted as evidence of a transient cytodifferentiating response elicited by the current. The fact that this type of electrical stimulation is capable of promoting both, differentiation and cell cycle arrest in human cancer cells, is of potential interest for a possible extension of the applications of CRET therapy towards the field of oncology.

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“…Preliminary tests of CRet system on cancer patients also showed consistent signs of slowing down the growth of the tumor tissues without adverse effects in the surrounding healthy tissues [20,21]. Additonally, previous studies have shown that CRet treatment induces cytostatic effects in the human hepatocarcinoma HepG2 [16,17,19], cytotoxic effects in NB69 human neuroblastoma cells [18] and significantly potentiate anticancer effect of 6-O-palmitoyl-ascorbate on human tongue squamous carcinoma HSC-4 [22].…”

Section: Methodsmentioning

confidence: 73%

“…It has been established that H 2 O 2 is involved in the redox control of several physiologic processes, including cell proliferation and apoptosis [32,33]. Furthermore, we previously reported that combined treatment with AsA and CRet increased ascorbate radical formation in HSC-4 cells [22]. Therefore, these results suggest that both H 2 O 2 and ascorbate radical generation are related to the effects of combined treatment with AsA and CRet through cell growth suppression because of G2/M arrest and apoptosis induction (see Fig.…”

Section: Discussionmentioning

confidence: 80%

“…EAT cells were seeded and preincubated for 24 h, and subsequently treated with medium containing 0.1-10 mM AsA, which was titrated with NaOH at pH 6.8-7.4, for 1 h to mimic the clinical intravenous infusion of AsA [23]. For CRet treatment, we used a CRet signal generator (INDIBA DH-308; INDI-BA S.A., Barcelona, Spain), which produces the electric currents of 0.45 MHz and thermal effects synergistically in tissues [22,24]. Exposure to CRet electric currents was achieved using pairs of stainless-steel electrodes designed ad hoc for in vitro stimulation ( Fig.…”

Section: Methodsmentioning

confidence: 99%

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Synergic Carcinostatic Effects of Ascorbic Acid and Hyperthermia on Ehrlich Ascites Tumor Cell

Saitoh¹,

Yoshimoto²,

Kato³

et al. 2015

Exp. Onc.

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Aim: In this study, we evaluated the carcinostatic effects of combined ascorbic acid (AsA) and a capacitive-resistive electric transfer (CRet) hyperthermic apparatus-induced hyperthermic treatment on Ehrlich ascites tumor (EAT) cells. Materials and Methods: EAT cells were exposed to various AsA (0–10 mM) concentrations for 1 h; they subsequently underwent CRet treatment for 15 min at 42 °C. Cell viability was assessed by the WST-8 assay 24 h after the combined treatment. Reactive oxygen species involvement was evaluated using catalase and tempol; caspase-3/7 activation was determined by their fluorescent substrates; cell proliferation were estimated by time-lapse observation. The effect on the cell cycle was analyzed by flow cytometry. Results: Combined AsA and CRet treatment synergistically suppressed cell viability compared with either treatment alone, and these synergistically carcinostatic effects were evident even at noncytotoxic concentrations of AsA alone (≤ 2 mM). The carcinostatic effects of combined AsA and CRet treatment were attenuated in a dose-dependent manner by catalase addition, but not by the superoxide anion radical scavenger tempol. Time-lapse observation revealed that combined AsA and CRet treatment activated caspase-3/7 at 10–24 h after treatment, accompanied by significant cell growth suppression. Cell cycle analysis revealed that the rate of sub-G1-phase (apoptotic) cells was drastically increased at 12 h and 24 h, and that the G2/M-phase cells gradually increased at 6–24 h after treatment. Conclusion: These results indicate that combined AsA and CRet treatment synergistically inhibits EAT cell growth through G2/M arrest and apoptosis induction via H2O2 generation at lower AsA concentrations; this carcinostatic effect cannot be exert ed by AsA alone.

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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

Cited by 19 publications

References 27 publications

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells

Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells

Molecular Mechanisms Underlying Antiproliferative and Differentiating Responses of Hepatocarcinoma Cells to Subthermal Electric Stimulation

Synergic Carcinostatic Effects of Ascorbic Acid and Hyperthermia on Ehrlich Ascites Tumor Cell

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