EXTH-05. TUMOR TREATING FIELDS IN COMBINATION WITH THE TERT-INHIBITOR ERIBULIN HAVE SYNERGISTIC ANTIPROLIFERATIVE EFFECTS ON HUMAN GLIOBLASTOMA CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi164-vi164
Author(s):  
Marco Stein ◽  
Piet Beusker ◽  
Hanna Goett ◽  
Malgorzata Kolodziej ◽  
Eberhard Uhl
Keyword(s):  
Cell Death ◽  
Combination Therapy ◽  
Synergistic Effect ◽  
Cell Lines ◽  
Combined Treatment ◽  
Antiproliferative Effects ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Established Cell ◽  
Human Gbm

Abstract OBJECTIVE Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The optimal combination therapy for Tumor Treating Fields (TTFields) in glioblastoma (GBM) treatment is unknown. The aim of our study was to analyze, the effects of the TERT-inhibitor eribulin in combination with TTFields on human GBM cells. METHODS Human GBM cells of the established cell lines U87, A172 and U251, and two patient-derived cell lines, were treated with eribulin monotherapy, TTFields monotherapy, or both modalities together. After 72 hours of therapy, cell counts were measured and clonogenic assays were performed. Annexin staining and fluorescence-activated cell scanning (FACS) was used to analyze cell death. RESULTS Overall surviving fractions were 39.8±11.0% for eribulin monotherapy, 32.2±23.9% for TTFields monotherapy, and 10.9±9.9% for the combined treatment. Mean observed annexin positive fractions were 11.2±8.2% (control), 28.6±9.7% (eribulin), 34.8±8.1% (TTFields), and 78.1±13.5% (combination), respectively. The mean clonogenic fractions over all cell lines were 25.9±7.8% for eribulin and 46.4±12.9% for TTFields. For the combination therapy, a synergistic effect with a decreased mean of 3.6% clonogenic fractions was observed. CONCLUSION Eribulin increases cell death and reduces clonogenicity our experiments. Additionally, a synergistic effect of the combined treatment of TTFields and eribulin synergistic was observed. Eribulin in combination with TTFields could be a new effective therapy for GBM.

scholarly journals Dexamethasone Treatment Limits Efficacy of Radiation, but Does Not Interfere With Glioma Cell Death Induced by Tumor Treating Fields

2021 ◽  
Vol 11 ◽  
Author(s):  
Benedikt Linder ◽  
Abigail Schiesl ◽  
Martin Voss ◽  
Franz Rödel ◽  
Stephanie Hehlgans ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Clinical Analysis ◽  
Concomitant Treatment ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Anti Cancer ◽  
Massive Cell Death ◽  
Human Gbm ◽  
Massive Cell

PurposeDexamethasone (Dex) is the most common corticosteroid to treat edema in glioblastoma (GBM) patients. Recent studies identified the addition of Dex to radiation therapy (RT) to be associated with poor survival. Independently, Tumor Treating Fields (TTFields) provides a novel anti-cancer modality for patients with primary and recurrent GBM. Whether Dex influences the efficacy of TTFields, however, remains elusive.MethodsHuman GBM cell lines MZ54 and U251 were treated with RT or TTFields in combination with Dex and the effects on cell counts and cell death were determined via flow cytometry. We further performed a retrospective analysis of GBM patients with TTFields treatment +/- concomitant Dex and analysed its impact on progression-free (PFS) and overall survival (OS).ResultsThe addition of Dex significantly reduced the efficacy of RT in U251, but not in MZ54 cells. TTFields (200 kHz/250 kHz) induced massive cell death in both cell lines. Concomitant treatment of TTFields and Dex did not reduce the overall efficacy of TTFields. Further, in our retrospective clinical analysis, we found that the addition of Dex to TTFields therapy did not influence PFS nor OS.ConclusionOur translational investigation indicates that the efficacy of TTFields therapy in patients with GBM and GBM cell lines is not affected by the addition of Dex.

Tandutinib (MLN518), a Potent FLT3 Inhibitor, Synergizes with Cytarabine and/or Daunorubicin in a Sequence-Independent Manner.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1374-1374 ◽  
Author(s):  
Marcus M. Schittenhelm ◽  
Kevin W. Yee ◽  
Kerstin M. Kampa ◽  
Michael C. Heinrich
Keyword(s):  
Combination Therapy ◽  
Synergistic Effect ◽  
Cell Lines ◽  
Induction Chemotherapy ◽  
Combined Treatment ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Comparable Efficacy ◽  
Flt3 Inhibitor

Abstract FLT3 kinase inhibitors display promising pre-clinical efficacy in a variety of in vitro and animal models of FLT3-ITD+ AML. Tandutinib is a 4-piprazinylquinazoline compound that is a potent inhibitor of type III RTKs with a cellular IC50 of ~200 nM for FLT3. In a phase 2 study, Tandutinib demonstrated anti-leukemic activity in approximately half of the evaluable patients, although there were no partial or complete remissions. Therefore, optimal use of like Tandutinib will likely require combination therapy with standard cytotoxic agents such as cytarabine (Cy) and an anthracycline (e.g. daunorubicin, Dn). Notably, single agent Tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. To determine the feasibility of combining Tandutinib and chemotherapy, we tested Tandutinib in combination with Cy and/or Dn. For our experiments, we utilized three cell lines containing FLT3 ITD mutations: a BaF3 cell line transduced with an ITD mutant FLT3 as well as MV 4–11 and MOLM 14 cell lines which have naturally occurring FLT3 ITD mutations. Data was analyzed using the statistical methods of Chou and Talalay to calculate combination indices (CI) for drug mixtures performed in a fixed dilution pattern. In all cell lines, calculated combination indices for inhibition of cellular proliferation and induction of apoptosis were much less than one, indicating a synergistic effect of combining Tandutinib with Cy or Dn. In addition, the combination of Tandutinib with Cy and Dn was also markedly synergistic. These results were confirmed using primary AML blasts (FLT3 ITD+). All of the above studies were performed using simultaneous treatment with Tandutinib and Cy and/or Dn. Previous in vitro studies utilizing a structurally unrelated FLT3 inhibitor, Lestaurtinib (CEP-701), demonstrated the potential importance of treatment sequencing for optimal killing of AML cells. Notably, treatment with Lestaurtinib with or following chemotherapy was found to be synergistic, whereas treatment with Lestaurtinib followed by chemotherapy was generally antagonistic. Therefore, we next determined whether sequencing of Tandutinib and chemotherapy had any effect on the efficacy of combination therapy. For these experiments, we tested two different sequencing regimens: monotherapy treatment with Tandutinib for 24 hours with the addition of Cy or Dn for an additional 48 hours; ormonotherapy with Cy or Dn for 24 hours with the addition of Tandutinib for an additional 48 hours. Both regimens produced a synergistic effect and had comparable efficacy. Therefore, unlike Lestaurtinib, the synergistic effect of Tandutinib and Cy/Dn appears to be independent of the sequence of drug administration. These data suggest that addition of Tandutinib to agents used in induction chemotherapy for AML could result in enhanced antileukemic effects. Our synergy experiments also suggest that combined use of Tandutinib and chemotherapy may allow dose reduction of chemotherapy (with resultant decreased side effects) without loss of antileukemic activity. Such a combined treatment approach may be particularly desirable for elderly AML patients who often have poor tolerance of standard AML chemotherapy regimens. Currently, the combination of Tandutinib + standard induction chemotherapy is being tested in a phase I/II study for treatment of newly diagnosed AML.

scholarly journals Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1878 ◽  
Author(s):  
Sami Znati ◽  
Rebecca Carter ◽  
Marcos Vasquez ◽  
Adam Westhorpe ◽  
Hassan Shahbakhti ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Cell Lines ◽  
Radiation Treatment ◽  
Combined Treatment ◽  
New Combination ◽  
Migration And Invasion ◽  
Syngeneic Mouse Model

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

scholarly journals Isobolographic Analysis Demonstrates the Additive and Synergistic Effects of Gemcitabine Combined with Fucoidan in Uterine Sarcomas and Carcinosarcoma Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 107 ◽  
Author(s):  
Marcin Bobiński ◽  
Karolina Okła ◽  
Jarogniew Łuszczki ◽  
Wiesława Bednarek ◽  
Anna Wawruszak ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Synergistic Effect ◽  
Cell Line ◽  
Cell Lines ◽  
Combined Treatment ◽  
Endometrial Stromal Sarcoma ◽  
Uterine Leiomyosarcoma ◽  
Uterine Sarcomas ◽  
Isobolographic Analysis ◽  
Stromal Sarcoma

Background: Uterine sarcomas and carcinosarcoma are associated with unfavorable prognosis. The regimens that are used in chemotherapy are associated with high incidence of side effects and usually do not significantly increase patients’ survival rates. In this study we investigated the activity and interactions between gemcitabine and fucoidan, the natural compound known for its anti-tumor properties, in human sarcomas and carcinosarcoma cell models. Methods: SK-UT-1, SK-UT1-B (carcinosarcoma), MES-SA (leiomyosarcoma), and ESS-1 (endometrial stromal sarcoma) cell lines were used for the experiments. Cells were incubated in the presence of gemcitabine, fucoidan, and mixtures, after the incubation the MTT tests were performed. In order to assess the interactions between tested compounds isobolographic analysis was performed. Additional assessments of apoptosis and cell cycle were done. Results: Additive effect of combined treatment with gemcitabine and fucoidan was observed in ESS-1 and SK-UT-1 cell line. Although the supra-additive (synergistic) effect noticed in SK-UT-1B cell line. It was not possible to determine the interactions of fucoidan and gemcitabine in MES-SA cell line due to insufficient response to treatment. Addition of fucoidan to gemcitabine enhances its proapoptotic activity, what was observed especially in ESS-1 and SK-UT-1B cell lines. The arrest of cell cycle induced by mixture of gemcitabine and fucoidan, superior comparing gemcitabine alone was observed in SK-UT-1B. Conclusions: Obtained data showed that a combination of fucoidan and gemcitabine in uterine endometrial stromal sarcoma and carcinosarcoma cell lines has additive or even synergistic effect in decreasing cell viability. Furthermore, this drug combination induces apoptosis and arrest of cell cycle. The resistance of uterine leiomyosarcoma cell line, justifies searching for other drugs combinations to improve therapy efficacy.

Intracellular NAD+ Depletion Enhances Bortezomib-Induced Myeloma Cytotoxicity

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 330-330
Author(s):  
Antonia Cagnetta ◽  
Michele Cea ◽  
Chirag Acharya ◽  
Teresa Calimeri ◽  
Yu-Tzu Tai ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effect ◽  
Cell Lines ◽  
Caspase 3 ◽  
Statistical Significance ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Nicotinamide Phosphoribosyltransferase

Abstract Abstract 330 Background: Our previous study demonstrated that inhibition of nicotinamide phosphoribosyltransferase (Nampt) acts by severely depleting intracellular NAD+ content and thus eliciting mitochondrial dysfunction and autophagic MM cell death. The proteasome inhibitor Bortezomib induces anti-MM activity by affecting a variety of signaling pathways. However, as with other agents, dose-limiting toxicities and the development of resistance limit its long-term utility. Here, we demonstrate that combining Nampt inhibitor and bortezomb induces synergistic anti-MM cell death both in vitro using MM cell lines or patient CD138+ MM cells and in vivo in a human plasmacytoma xenograft mouse model. Material and Methods: We utilized MM.1S, MM.1R, RPMI-8226, and U266 human MM cell lines, as well as purified tumor cells from patients relapsing after prior therapies. Cell viability and apoptosis assays were performed using Annexin V/PI staining. Intracellular NAD+ level and proteasome activity were quantified after 12, 24, and 48h exposure to single/combination drugs by specific assays. In vitro angiogenesis was assessed by Matrigel capillary-like tube structure formation assay. Immunoblot analysis was performed using antibodies to caspase-8, caspase-9, caspase-3, PARP, Bcl-2, and tubulin. CB-17 SCID male mice (n = 28; 7 mice/EA group) were subcutaneously inoculated with 5.0 × 106 MM.1S cells in 100 microliters of serum free RPMI-1640 medium. When tumors were measurable (3 weeks after MM cell injection), mice were treated for three weeks with vehicle alone, FK866 (30mg/kg 4 days weekly), Bortezomib (0.5 mg/kg twice weekly), or FK866 (30 mg/kg) plus Bortezomib (0.5 mg/kg). Statistical significance of differences observed in FK866, Bortezomib or combination-treated mice was determined using a Student t test. Isobologram analysis was performed using “CalcuSyn” software program. A combination index < 1.0 indicates synergism. Results/Discussion: Combining FK866 and Bortezomib induces synergistic anti-MM activity in vitro against MM cell lines (P<0.005, CI < 1) or patient CD138-positive MM cells (P< 0.004). FK866 plus Bortezomib-induced synergistic effect is associated with: 1)activation of caspase-8, caspase-9, caspase-3, and PARP; 2) improved intracellular NAD+ dissipation; 3) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteolytic activities; 4) inhibition of NF-kappa B signaling; and 5) inhibition of angiogenesis. Importantly, the ectopic overexpression of Nampt rescues this observed synergistic effect; conversely, Nampt knockdown by RNAi significantly enhances the anti-MM effect of bortezomib. In the murine xenograft MM model, low dose combination FK866 (30 mg/kg) and Bortezomib (0.5 mg/kg) is well tolerated, significantly inhibits tumor growth (P < 0.001), and prolongs host survival (2–2.5 months in mice receiving combined drugs, P = 0.001). These findings demonstrate that intracellular NAD+ levels represent a major determinant in the ability of bortezomib to induce apoptosis of MM cells, providing the rationale for clinical protocols evaluating FK866 together with Bortezomib to improve patient outcome in MM. Disclosures: Munshi: Celgene: Consultancy; Millenium: Consultancy; Merck: Consultancy; Onyx: Consultancy.

The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4322-4329 ◽  
Author(s):  
Ebenezer David ◽  
Shi-Yong Sun ◽  
Edmund K. Waller ◽  
Jing Chen ◽  
Fadlo R. Khuri ◽  
...  
Keyword(s):  
Cell Death ◽  
Combination Therapy ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Single Agent ◽  
Myeloma Cell ◽  
Tumor Cell Death ◽  
Down Regulation ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor

The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor (bortezomib, Velcade, PS-341) would enhance myeloma-cell killing. MM cell lines and primary human cells were used to test either single agent bortezomib, lonafarnib, or the combination on MM signaling and apoptosis. Combination therapy induced synergistic tumor-cell death in MM cell lines and primary MM plasma cells. Cell death was rapid and associated with increased caspase 3, 8, and 9 cleavage and concomitant down-regulation of p-AKT. Down-regulation of p-AKT was seen only in combination therapy and not seen with either single agent. Cells transfected with constitutively active p-AKT, wild-type AKT, or Bcl-2 continued to demonstrate synergistic cell death in response to the combination. The order of addition was critically important, supporting bortezomib followed by lonafarnib as the optimal schedule. The combination of a proteasome inhibitor and farnesyl transferase inhibitor demonstrates synergistic myeloma-cell death and warrants further preclinical and clinical studies.

scholarly journals Proton pump inhibitors enhance chemosensitivity, promote apoptosis, and suppress migration of breast cancer cells

2020 ◽  
Vol 70 (2) ◽  
pp. 179-190 ◽  
Author(s):  
Worood G. Ihraiz ◽  
Mamoun Ahram ◽  
Sanaa K. Bardaweel
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Synergistic Effect ◽  
Cancer Cells ◽  
Cell Lines ◽  
Proton Pump ◽  
Breast Cancer Cells ◽  
Combined Treatment ◽  
Combined Effects ◽  
Mcf 7

AbstractBreast cancer is the most common cancer and is the leading cause of cancer deaths among women worldwide. Despite the availability of numerous therapeutics for breast cancer management, cytotoxicity and emergence of drug resistance are major challenges that limit their benefits. The acidic microenvironment surrounding tumor cells is a common feature inducing cancer cell invasiveness and chemoresistance. Proton pump inhibitors (PPIs) are one of the most commonly prescribed drugs for the treatment of acid-related conditions. PPIs have been reported to exhibit antitumorigenic effects in many cancer types. In this study, the anti-proliferative and anti-migratory effects of PPIs in three breast cancer cell lines; MCF-7, T47D, and MDA-MB-231 cells, have been investigated. In addition, the combined effects of PPIs with anticancer drugs, as well as the mechanism of PPI-mediated anti-proliferative activity were evaluated. The anti-proliferative and combined effects of PPIs were evaluated by MTT assay. Cell migration was assessed using the wound-healing assay. The mechanism of cell death was assessed using annexin V-FITC/propidium iodide staining flow cytometry method. Our results indicated that PPIs treatment significantly inhibited the growth of breast cancer cells in a dose-dependent manner. The antiproliferative activity of PPIs was significantly induced by apoptosis in all tested cell lines. The combined treatment of PPIs with doxorubicin resulted in a synergistic effect in all cell lines, whereas the combined treatment with raloxifene exhibited synergistic effect in T47D cells only and additive effects in MDA-MB-231 and MCF-7 cells. In addition, PPIs treatment significantly reduced cell migration in MDA-MB-231 cells. In conclusion, the addition of PPIs to the treatment regimen of breast cancer appears to be a promising strategy to potentiate the efficacy of chemotherapy and may suppress cancer metastasis.

The combined treatment of 150 kHz tumor treating fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro and in vivo.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15653-e15653 ◽  
Author(s):  
Uri Weinberg ◽  
Shiri Davidi ◽  
Catherine Tempel- Brami ◽  
Mijal Munster ◽  
Karnit Gotlib ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combined Treatment ◽  
Control Group ◽  
Multikinase Inhibitor ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Drug Concentrations ◽  
Clonogenic Potential ◽  
Hcc Cells

e15653 Background: Hepatocellular carcinoma (HCC) is the third cause of cancer related mortality and the primary cause of cancer death. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. Sorafenib, an oral multikinase inhibitor is approved for patients with advanced HCC, yet its survival benefit is still limited. In this work we explored the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. Methods: HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib (36-3000 nM) was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined. TTFields (1.2 V/cm) and Sorafenib (10 mg/kg) were applied for 6 days to rats injected to the liver with N1S1 HCC cells. Tumor growth was followed using MRI. Results: The optimal TTFields frequency was 150 kHz for both cell lines. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 36-40% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number of cells (p < 0.001) as compared to each treatment alone. The averaged tumor volume fold increase of the combination treatment group was significantly lower than the one observed in the: control group, the TTFields group and the Sorafenib group. Conclusions: The results presented in this work demonstrate that TTFields can be an effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy.

In vitro and in vivo efficacy of the combined treatment of 150 khz tumor treating fields (TTFields) and sorafenib in hepatocellular carcinoma.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 333-333
Author(s):  
Uri Weinberg ◽  
Shiri Davidi ◽  
Karnit Gotlib ◽  
Einav Zeevi ◽  
Catherine Tempel- Brami ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Combined Treatment ◽  
Control Group ◽  
Multikinase Inhibitor ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Drug Concentrations ◽  
Clonogenic Potential ◽  
Hcc Cells

333 Background: Hepatocellular carcinoma (HCC) is the third cause of cancer related mortality and the primary cause of cancer death. Sorafenib, an oral multikinase inhibitor is approved for patients with advanced HCC, yet its survival benefit is still limited. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. The aim of this work is to explore the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. Methods: HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib (36-3000 nM) was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined. N1S1 HCC cells were injected to the left lobe of the liver of SD rats. After 1 week, TTFields (1.2 V/cm) and Sorafenib (10 mg/kg) were applied for 6 days and tumor growth was followed using MRI. Healthy rats were used to study safety of the use of TTFields (150 kHz) applied to the abdomen. Results: The optimal TTFields frequency was found to be 150 kHz for both cell lines. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 53-64% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number cells (2-way ANOVA, p < 0.001) as compared to each treatment alone. Tumor growth was significantly reduced by the combined group compared to the control group (student t test, p < 0.01). Safety studies did not reveal any adverse event associated with TTFields application to the rat abdomen. Conclusions: The results presented in this work demonstrate that TTFields can be a safe and effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy.

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