Research Abstracts Showing the Synergistic Effects Between Pulsed Fields and Chemotherapy

Since the paper was written in 2004, more supporting published references to the effect have been discovered. Some have been published as recently as March of 2006. As more references are discovered or published, they will be added to this web page.

BMC Cancer. 2006 Mar 17;6:72.

Alternating current electrical stimulation enhanced chemotherapy: a novel strategy to bypass multidrug resistance in tumor cells.

Janigro D, Perju C, Fazio V, Hallene K, Dini G, Agarwal MK, Cucullo L.

Division of Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44106, USA. janigrd@ccf.org

BACKGROUND: Tumor burden can be pharmacologically controlled by inhibiting cell division and by direct, specific toxicity to the cancerous tissue. Unfortunately, tumors often develop intrinsic pharmacoresistance mediated by specialized drug extrusion mechanisms such as P-glycoprotein. As a consequence, malignant cells may become insensitive to various anti-cancer drugs. Recent studies have shown that low intensity very low frequency electrical stimulation by alternating current (AC) reduces the proliferation of different tumor cell lines by a mechanism affecting potassium channels while at intermediate frequencies interfere with cytoskeletal mechanisms of cell division. The aim of the present study is to test the hypothesis that permeability of several MDR1 over-expressing tumor cell lines to the chemotherapic agent doxorubicin is enhanced by low frequency, low intensity AC stimulation. METHODS: We grew human and rodent cells (C6, HT-1080, H-1299, SKOV-3 and PC-3) which over-expressed MDR1 in 24-well Petri dishes equipped with an array of stainless steel electrodes connected to a computer via a programmable I/O board. We used a dedicated program to generate and monitor the electrical stimulation protocol. Parallel cultures were exposed for 3 hours to increasing concentrations (1, 2, 4, and 8 microM) of doxorubicin following stimulation to 50 Hz AC (7.5 microA) or MDR1 inhibitor XR9576. Cell viability was assessed by determination of adenylate kinase (AK) release. The relationship between MDR1 expression and the intracellular accumulation of doxorubicin as well as the cellular distribution of MDR1 was investigated by computerized image analysis immunohistochemistry and Western blot techniques. RESULTS: By the use of a variety of tumor cell lines, we show that low frequency, low intensity AC stimulation enhances chemotherapeutic efficacy. This effect was due to an altered expression of intrinsic cellular drug resistance mechanisms. Immunohistochemical, Western blot and fluorescence analysis revealed that AC not only decreases MDR1 expression but also changes its cellular distribution from the plasma membrane to the cytosol. These effects synergistically contributed to the loss of drug extrusion ability and increased chemo-sensitivity. CONCLUSION: In the present study, we demonstrate that low frequency, low intensity alternating current electrical stimulation drastically enhances chemotherapeutic efficacy in MDR1 drug resistant malignant tumors. This effect is due to an altered expression of intrinsic cellular drug resistance mechanisms. Our data strongly support a potential clinical application of electrical stimulation to enhance the efficacy of currently available chemotherapeutic protocols.

PMID: 16545134

1: Anticancer Res. 2001 Jan-Feb;21(1A):317-20.

Drug resistance modification using pulsing electromagnetic field stimulation for multidrug resistant mouse osteosarcoma cell line.

Hirata M, Kusuzaki K, Takeshita H, Hashiguchi S, Hirasawa Y, Ashihara T.

Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.

Multidrug resistance (MDR) is one of the major problems in osteosarcoma chemotherapy. Therefore, methods of overcoming MDR are urgently needed. In this study, we investigated the effects of pulsing electromagnetic field stimulation (PEMFs) on a MDR murine osteosarcoma cell line which strongly expresses P-glycoprotein (P-gp). To assess the reversal effects of PEMFs on doxorubicin (DOX) resistance, MTT assay was applied. Viable cells were assessed by the trypan blue exclusion test. Fluorescence intensity of DOX binding to nuclear DNA of each cell was measured using a cytofluorometer. Changes in P-gp expression in each cell were detected by the indirect immunofluorescence method using an antibody to Pgp. PEMFs increased DOX binding ability to nuclear DNA and inhibited cell growth, although it had no significant effect on P-gp expression. These findings indicated that PEMFs reversed the DOX resistance of the MOS/ADR1 cells by inhibiting P-gp function. The results suggested that PEMFs may be useful as a local treatment for MDR osteosarcoma.

PMID: 11299755

1: Radiats Biol Radioecol. 2003 May-Jun;43(3):351-4.

[Antitumor effect of joint action of low intensity electromagnetic fields and ultra low doses of doxorubicin]

[Article in Russian]

Ostrovskaia LA, Budnik MI, Korman DB, Bliukhterova NV, Fomina MM, Rykova VA, Burlakova EB.

Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119991 Russia. l.ostrovskaya@chph.ras.ru

Combined action of a low intensive physical factor and a chemotherapeutic agent in ultralow doses against Lewis lung carcinoma was studied. Antitumor activity of low intensiwe electromagnetic field was expressed as inhibition of tumor growth at 60% compare to control. Ultra low doses of doxorubicin as well as its standard dose resulted in inhibition of tumor growth by 60-70% in comparison with control. Joint action of both factors leaded to increasing in the antitumor effect that reached such level of tumor growth inhibition as 85% relative to control.

PMID: 12881995

Cancer Biochem Biophys. 1999 Jul;17(1-2):89-98.

Magnetic field induced inhibition of human osteosarcoma cells treated with adriamycin.

Chakkalakal DA, Mollner TJ, Bogard MR, Fritz ED, Novak JR, McGuire MH.

Creighton University Biomedical Engineering Center, Creighton University School of Medicine, Omaha, NE 68105, USA.

Morbidity resulting from the toxicity of chemotherapeutic drugs suggests that novel approaches are worthy of investigation. Development of the use of low intensity magnetic fields as an adjuvant to current treatment regimens to prevent metastatic disease may prove to be efficacious. Using a cell culture model, we have developed a magnetic field (MF) treatment that offers the possibility of lowering the therapeutic dose of these drugs and thereby reducing morbidity. Our studies have found that a low intensity (approximately 2 gauss) MF signal and a relatively low dose (0.1 microg/ml) of Adriamycin (ADR) inhibited proliferation of human osteosarcoma cells by 82%, whereas the MF and ADR acting individually caused only 19% and 44% inhibition, respectively.

PMID: 10738905

Bioelectromagnetics. 2002 Dec;23(8):578-85.

Influence of 1 and 25 Hz, 1.5 mT magnetic fields on antitumor drug potency in a human adenocarcinoma cell line.

Ruiz-Gomez MJ, de la Pena L, Prieto-Barcia MI, Pastor JM, Gil L, Martinez-Morillo M.

Laboratory of Radiobiology, Department of Radiology and Physical Medicine, Faculty of Medicine, University of Malaga, Teatinos, Malaga, Spain.

The resistance of tumor cells to antineoplastic agents is a major obstacle during cancer chemotherapy. Many authors have observed that some exposure protocols to pulsed electromagnetic fields (PEMF) can alter the efficacy of anticancer drugs; nevertheless, the observations are not clear. We have evaluated whether a group of PEMF pulses (1.5 mT peak, repeated at 1 and 25 Hz) produces alterations of drug potency on a multidrug resistant human colon adenocarcinoma (HCA) cell line, HCA-2/1(cch). The experiments were performed including (a) exposures to drug and PEMF exposure for 1 h at the same time, (b) drug exposure for 1 h, and then exposure to PEMF for the next 2 days (2 h/day). Drugs used were vincristine (VCR), mitomycin C (MMC), and cisplatin. Cell viability was measured by the neutral red stain cytotoxicity test. The results obtained were: (a) The 1 Hz PEMF increased VCR cytotoxicity (P < 0.01), exhibiting 6.1% of survival at 47.5 microg/ml, the highest dose for which sham exposed groups showed a 19.8% of survival. For MMC at 47.5 microg/ml, the % of survival changed significantly from 19.2% in sham exposed groups to 5.3% using 25 Hz (P < 0.001). Cisplatin showed a significant reduction in the % of survival (44.2-39.1%, P < 0.05) at 25 Hz and 47.5 microg/ml, and (b) Minor significant alterations were observed after nonsimultaneous exposure of cells to PEMF and drug. The data indicate that PEMF can induce modulation of cytostatic agents in HCA-2/1(cch), with an increased effect when PEMF was applied at the same time as the drug. The type of drug, dose, frequency, and duration of PEMF exposure could influence this modulation. Copyright 2002 Wiley-Liss, Inc.

PMID: 12395412

1: J Environ Pathol Toxicol Oncol. 1993 Oct-Dec;12(4):193-7.

Biological effects of PEMF (pulsing electromagnetic field): an attempt to modify cell resistance to anticancer agents.

Pasquinelli P, Petrini M, Mattii L, Galimberti S, Saviozzi M, Malvaldi G.

C.R.E.S.A.M., Pisa, Italy.

Pulsing Electromagnetic Field (PEMF) effects lead to a modification of the multidrug resistance (MDR) of cells in vitro and in vivo. The murine leukemic doxorubicin-resistant cell line, P388/Dx, subjected to PEMF irradiation in vitro, showed a significant difference in thymidine incorporation when the concentration of doxorubicin reached a level of 1 microgram/mL, which corresponds to the inhibition dose 50 (ID50). The human lymphoblastic leukemia vinblastine-resistant cell line, CEM/VLB100, also showed a significant modification under the same experimental conditions at the in vitro ID50 corresponding to a vinblastine concentration of 100 ng/mL. BDF1 mice transplanted with P388/Dx cells also had an increase in their life span when doxorubicin was injected intraperitoneally in fractionated doses, while being subjected to PEMF irradiation.

PMID: 8189374

1: Pharmacol Res. 2003 Jul;48(1):83-90.

Static and ELF magnetic fields enhance the in vivo anti-tumor efficacy of cis-platin against lewis lung carcinoma, but not of cyclophosphamide against B16 melanotic melanoma.

Tofani S, Barone D, Berardelli M, Berno E, Cintorino M, Foglia L, Ossola P, Ronchetto F, Toso E, Eandi M.

Department of Medical Physics, Ivrea Hospital, ASL 9, 10015 (TO), Ivrea, Italy.

Previous works showed that exposure to static and extremely low frequency (ELF) magnetic fields (MF) over 3 mT slows down the growth kinetics of human tumors engrafted s.c. in immunodeficient mice, reducing their metastatizing power and prolonging mouse survival. In the experiments reported here, immunocompetent mice bearing murine Lewis Lung carcinomas (LLCs) or B16 melanotic melanomas were exposed to MF and treated respectively with two commonly used anti-cancer drugs: cis-diamminedichloroplatinum (cis-platin) and N,N-bis (2-chloroethyl)tetra-hydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (cyclophosphamide). The experiment endpoint was survival time. The survival time of mice treated with cis-platin (3mg/kg i.p.) and exposed to MF was significantly (P<0.01) longer than that of mice treated only with cis-platin or only exposed to MF, superimposing that of mice treated with 10mg/kg i.p. of the drug, showing that MF act synergically with the pharmacological treatment. On the contrary, when mice treated with cyclophosphamide (50mg/kg i.p.) were exposed to MF no synergic effects were observed, the survival curve being exactly the same as that of mice treated with the drug alone. No clinical signs or toxicity were seen in any of the mice exposed to MF alone or along with cis-platin or cyclophosphamide treatment, compared to mice given only the two known drugs.A possible explanation for the synergic effect of MF being found in mice treated with cis-platin could be that the platinum ion stimulates radical production and that MF enhance active oxygen production bringing about changes in tumor cell membrane permeability, influencing positively the drug uptake. Alternatively, or in addition to this, it has been demonstrated that the rate of conversion of cis-platin to reactive species able to bind to DNA, is increased by localized production of free radicals by MF.

PMID: 12770519

Pulsed EM fields not only enhance the effects of chemotherapeutic medications, they can also enhance the effects of antibiotics.

J Bone Joint Surg Br. 2003 May;85(4):588-93.

Electromagnetic augmentation of antibiotic efficacy in infection of orthopaedic implants.

Pickering SA, Bayston R, Scammell BE.

Academic Department of Orthopaedic and Fracture Surgery, Queen's Medical Centre, Nottingham, England, UK.

Infection of orthopaedic implants is a significant problem, with increased antibiotic resistance of adherent 'biofilm' bacteria causing difficulties in treatment. We have investigated the in vitro effect of a pulsed electromagnetic field (PEMF) on the efficacy of antibiotics in the treatment of infection of implants. Five-day biofilms of Staphylococcus epidermidis were grown on the tips of stainless-steel pegs.They were exposed for 12 hours to varying concentrations of gentamicin or vancomycin in microtitre trays at 37 degrees C and 5% CO2. The test group were exposed to a PEMF. The control tray was not exposed to a PEMF. After exposure to antibiotic the pegs were incubated overnight, before standard plating onto blood agar for colony counting. Exposure to a PEMF increased the effectiveness of gentamicin against the five-day biofilms of Staphylococcus epidermidis. In three of five experiments there was reduction of at least 50% in the minimum biofilm inhibitory concentration. In a fourth experiment there was a two-log difference in colony count at 160 mg/l of gentamicin. Analysis of variance (ANOVA) confirmed an effect by a PEMF on the efficacy of gentamicin which was significant at p < 0.05. There was no significant effect with vancomycin.

PMID: 12793569

Antimicrob Agents Chemother. 1996 Sep;40(9):2012-4.

Bacterial biofilms and the bioelectric effect.

Wellman N, Fortun SM, McLeod BR.

Engineering Research Center, Department of Electrical Engineering, Montana State University, Bozeman 59717-0378, USA.

Bacterial biofilms are acknowledged to be a major factor in problems of ineffective sterilization often encountered in clinics, hospitals, and industrial processes. There have been indications that the addition of a relatively small direct current electric field with the sterilant used to combat the biofilm greatly increases the efficacy of the sterilization process. The results of the experiments reported in this paper support the concept of the "bioelectric effect" as reported by J.W. Costerton, B. Ellis, K. Lam, F. Johnson, and A.E. Khoury (Antimicrob. Agents Chemother, 38:2803-2809, 1994). With a current of 1 mA flowing through the chamber containing the biofilm, an increase in the killing of the bacteria of about 8 log orders was observed at the end of 24 h (compared with the control with the same amount of antibacterial agent but no current). We also confirmed that the current alone does not affect the biofilm and that there appear to be optimum levels of both the current and the sterilant that are needed to obtain the maximum effect.

PMID: 8878572 [PubMed - indexed for MEDLINE]

Antimicrob Agents Chemother. 2004 Dec;48(12):4662-4.

A radio frequency electric current enhances antibiotic efficacy against bacterial biofilms.

Caubet R, Pedarros-Caubet F, Chu M, Freye E, de Belem Rodrigues M, Moreau JM, Ellison WJ.

Unite Securite Microbiologique des Aliments, Institut des Sciences et Techniques des Aliments de Bordeaux, Universite de Bordeaux 1, Talence, France. r.caubet@istab.u-bordeaux1.fr

Bacterial biofilms are notably resistant to antibiotic prophylaxis. The concentration of antibiotic necessary to significantly reduce the number of bacteria in the biofilm matrix can be several hundred times the MIC for the same bacteria in a planktonic phase. It has been observed that the addition of a weak continuous direct electric current to the liquid surrounding the biofilm can dramatically increase the efficacy of the antibiotic. This phenomenon, known as the bioelectric effect, has only been partially elucidated, and it is not certain that the electrical parameters are optimal. We confirm here the bioelectric effect for Escherichia coli biofilms treated with gentamicin and with oxytetracycline, and we report a new bioelectric effect with a radio frequency alternating electric current (10 MHz) instead of the usual direct current. None of the proposed explanations (transport of ions within the biofilm, production of additional biocides by electrolysis, etc.) of the direct current bioelectric effect are applicable to the radio frequency bioelectric effect. We suggest that this new phenomenon may be due to a specific action of the radio frequency electromagnetic field upon the polar parts of the molecules forming the biofilm matrix.

PMID: 15561841

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