scholarly journals EXTH-69. INCREASED CANCER CELL PERMEABILITY FOLLOWING TUMOR TREATING FIELDS (TTFIELDS) APPLICATION IN VITRO

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii102-ii102
Author(s):  
Tali Voloshin ◽  
Yaara Porat ◽  
Noa Kaynan ◽  
Anat Klein-Goldberg ◽  
Rom Paz ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cell Permeability ◽  
Intracellular Accumulation ◽  
Optimal Frequency ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Cellular Permeability ◽  
Resistant Cells

Abstract INTRODUCTION Tumor Treating Fields (TTFields), encompassing alternating electric fields within the intermediate frequency range, is an anticancer treatment delivered to the tumor region through transducer arrays placed non-invasively on the skin. This novel loco-regional treatment has demonstrated efficacy and safety and is FDA-approved in patients with glioblastoma (GBM) and malignant pleural mesothelioma. TTFields are currently being investigated in other solid tumors in ongoing trials. Recently, TTFields were reported to alter the cellular membrane structure of GBM cells, rendering them more permeable. The objective of this study was to characterize TTFields-induced cellular permeability in cancerous cell lines. METHODS TTFields were applied to uterine sarcoma, glioblastoma, and breast adenocarcinoma cell lines across a range of frequencies (50–500 kHz). Cellular permeability was assessed by quantifying the percentages of cells with accumulated 7-aminoactinomycin D (7-AAD) using flow cytometry and cytotoxicity was assessed based on cell counts. Kinetics were determined using different 7-AAD exposure times relative to TTFields treatment end. Changes in intracellular accumulation of anthracycline chemotherapeutics were evaluated in chemotherapy-sensitive and chemotherapy-resistant cells. RESULTS TTFields induced cellular permeability to 7-AAD in all 4 cancer cell lines tested. The optimal frequency for TTFields-induced cellular permeability was different from the optimal cytotoxic frequency. Kinetics measurements demonstrated that TTFields-induced permeability is transient and is effective only during application of TTFields. In combination experiments, TTFields improved intracellular accumulation of chemotherapeutic agents. Furthermore, combining chemotherapy with TTFields treatment facilitated accumulation of chemotherapeutics in chemotherapy-resistant cells to levels comparable with accumulation in chemotherapy-sensitive cancer cells. CONCLUSIONS This study demonstrates that TTFields can transiently increase cancer cell permeability in vitro with an optimal frequency that is variable from the frequency that is used to induce cancer cell cytotoxicity. Moreover, this effect is reversible and cellular permeability is restored to a normal state upon TTFields treatment cessation.

EXTH-74. INCREASING CANCER CELL MEMBRANE PERMEABILITY THROUGH APPLICATION OF TUMOR TREATING FIELDS (TTFIELDS)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi180-vi180
Author(s):  
Tali Voloshin ◽  
Bella Koltun ◽  
Lilach Koren ◽  
Yaara Porat ◽  
Alexandra Volodin ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Membrane Permeability ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Permeability ◽  
Cell Membrane Permeability ◽  
Intracellular Accumulation ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Resistant Cells

Abstract INTRODUCTION Tumor Treating Fields (TTFields) are intermediate frequency, alternating electric fields with anti-mitotic effects on cancerous cells. TTFields are delivered non-invasively through arrays placed on the skin at the tumor region. TTFields therapy is approved in several territories for treatment of glioblastoma (GBM) and mesothelioma. Recently, TTFields have been shown to increase GBM cell membrane permeability. The current study aimed to explore this effect in multiple cell lines and examine the potential benefits of combining TTFields with other anticancer agents. METHODS TTFields were delivered to GBM (U-87 MG), uterine sarcoma (MES-SA), and breast adenocarcinoma (MCF-7) cell lines for 72hr across a range of frequencies (50-500kHz). Cytotoxicity of TTFields was examined by cell counts, and intracellular accumulation of 7-aminoactinomycin D (7-AAD) was measured by flow cytometry. Exposing the cells to 7-AAD at different time points relative to TTFields application cessation was used to determine the kinetics of cell membrane permeability. The potential of TTFields to facilitate intracellular accumulation of anthracycline chemotherapeutics was tested in chemotherapy-sensitive and chemotherapy-resistant cells. RESULTS Elevated intracellular accumulation of 7-AAD was observed in all examined cell lines treated with TTFields, at an optimal frequency that differed from that for maximal TTFields-induced cytotoxicity. No intracellular accumulation of 7-AAD was seen for measurements performed after termination of TTFields application, indicating that increased cell membrane permeability by TTFields was temporary and reversible. Lastly, the accumulation of chemotherapeutic agents in chemotherapy-resistant cancer cells was elevated to the same extent as in matched chemotherapy-sensitive cells when TTFields were delivered concomitant with chemotherapy. CONCLUSIONS TTFields increased cancer cell permeability in a transient and reversible manner across multiple cancer cell types. The increased permeability enhanced intracellular accumulation of chemotherapeutics, even within chemotherapy-resistant cells.

scholarly journals P11.20 Assessing TTFields-response and associated gene expression in various human cancer cell lines

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii46-iii47
Author(s):  
A Kinzel ◽  
G Lavy-Shahaf ◽  
M Giladi ◽  
R Schneiderman ◽  
K Gotlib ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Synergistic Effects ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Optimal Frequency ◽  
Human Cancer Cell Lines ◽  
Cell Counts

Abstract BACKGROUND Various cancer cell lines were reported to be affected in an inhibitory manner of varying magnitude by tumor treating fields (TTFields). Here, we aimed to detect response markers for TTFields treatment by analyzing specific properties of cell lines according to their response pattern to these alternating electric fields of intermediate frequency and low intensity. MATERIAL AND METHODS We treated 45 cell lines of diverse types of human cancer with TTFields at their specific optimal frequency and equal nominal intensity of 1.7 V/cm for 72 h. In addition to investigating cytotoxicity and clonogenic potential, we used the Cancer Cell Line Encyclopedia (CCLE) database for further analysis: First, to functionally examine patterns of differentially expressed genes or mutations associated with response to TTFields; and second, to compare sensitivity to TTFields using pharmacological profiling (CCLE). RESULTS TTFields had a cytotoxic effect on tested cell lines of 50 % on average (range: 14–86% reduced cell counts), whereas the clonogenic effect varied between no effect and 88 % reduction in the number of colonies. With regard to differential gene expression and mutation analysis, our analysis detected upregulated pathways associated with migration, DNA damage repair response, oxidative stress, and hypoxia. Further, cells identified as having a better response to TTFields were also more sensitive to lapatinib, PHA-665752 and PLX-4720. CONCLUSION In this study, we determined the optimal frequency for maximum response to TTFields in numerous human cancer cell lines. Our results argue strongly for a vast effectiveness of TTFields treatment in cancer cells, and synergistic effects in combination with other therapeutic agents might be revealed in future studies using pharmacological profiling. Beyond that, further research is needed on the role of identified response-associated mutations.

Abstract 5848: Tumor treating fields (TTFields) induce cancer cell permeability in vitro

2020 ◽  
Author(s):  
Tali Voloshin ◽  
Yaara Porat ◽  
Noa Kaynan ◽  
Anat Klein-Goldberg ◽  
Rom Paz ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Permeability ◽  
Tumor Treating Fields

scholarly journals EXTH-34. IN VITRO TUMOR TREATING FIELDS (TTFIELDS) APPLIED PRIOR TO RADIATION ENHANCES THE RESPONSE TO RADIATION IN PATIENT-DERIVED GLIOBLASTOMA CELL LINES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi89-vi89
Author(s):  
Sharon Michelhaugh ◽  
Sandeep Mittal
Keyword(s):  
Cell Lines ◽  
Crystal Violet ◽  
Clonogenic Assay ◽  
Recurrent Glioblastoma ◽  
Control Group ◽  
Newly Diagnosed ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Newly Diagnosed Glioblastoma

Abstract Tumor treating fields are FDA-approved for treatment of newly-diagnosed and recurrent glioblastoma. Adding TTFields therapy to standard-of-care extended progression-free survival and overall survival in newly-diagnosed glioblastoma patients. In this study, cell lines generated from newly-diagnosed glioblastoma patients were treated in vitro with TTFields prior to irradiation to determine if the response to radiation would be altered. This study was approved by the WSU Institutional Review Board and written consent obtained from the patients. Single-cell suspensions generated from tumor tissues obtained from newly-diagnosed patients were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields initiation, cells were plated on plastic coverslips (5×104cells/coverslip) and incubated overnight. Then, TTFields were applied at 200 kHz with a field intensity of ~1.6 V/cm for 3 days. After TTFields application, cells were irradiated with 2, 4, or 6 Gy, or were untreated. After radiation delivery, cells were harvested and replated in a clonogenic assay. From each group, 3 coverslips were each replated in triplicate. After 3 days (3 doubling times), cells were stained with crystal violet and plates were scanned to determine cell counts. Treatment groups were compared to their control group with t-test. For both patient-derived GBM cell lines tested, TTFields prior to radiation decreased the number of crystal violet-stained cells in the clonogenic assay plates. In cell line 15–037, pretreatment with TTFields decreased cell counts by 16, 29, and 56% after 2, 4, or 6 Gy radiation, respectively, compared to the control cells with no TTFields pretreatment (p< 0.05). The response in 14-015S cells was less radiation dose-dependent, with the decrease in cell counts ranging from 33–47% control across the radiation doses (p< 0.05). These data suggest that the use of TTFields therapy prior to radiotherapy may enhance the response to radiotherapy in GBM patients.

Inhibition of histone lysine demethylases with TACH101, a first-in-class pan-inhibitor of KDM4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3105-3105
Author(s):  
Chandtip Chandhasin ◽  
Sanghee Yoo ◽  
Joselyn Del Rosario ◽  
Young K Chen ◽  
Jeffrey Stafford ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cell Permeability ◽  
Multiple Cancer ◽  
Histone Lysine ◽  
Histone Lysine Demethylases

3105 Background: The KDM4 family of histone lysine demethylases consists of four main isoforms (KDM4A, B, C, D), all of which have been identified as key oncogenic drivers. They function as epigenetic regulators and control transitions between transcriptionally silent and active chromatin states via removal of methyl marks on histone H3K9 and histone H3K36. KDM4 isoforms play an important role in the epigenetic dysregulation in various cancers and is linked to more aggressive disease and poorer clinical outcomes. Functional redundancy and cross-activity have been observed across KDM4 family members, thus, selective inhibition of one isoform appears to not be effective. TACH101 is a novel, first-in-class pan inhibitor of KDM4 that simultaneously targets multiple isoforms of KDM4. Here we present data that show TACH101 has promising pre-clinical and pharmacologic properties as a cancer therapeutic. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell-proliferation assays in multiple cancer cell lines, apoptotic and cell cycle analyses, and efficacy studies in various xenograft tumor models and patient-derived organoid models. Results: In vitro, TACH101 was broadly effective in killing 67% (200 out of 300) of cancer cell lines screened. TACH101 demonstrated potent increase of H3K36me3 levels (EC50 < 0.001 mM, HTRF) in KYSE-150 cell line engineered to overexpress KDM4C and potent anti-proliferative activity in multiple cell lines in OncoPanel. TACH101 treatment increased cancer cell population in S-phase in multiple cancer cell lines indicating cell-cycle arrest. TACH101 induced apoptosis in human colorectal (HT-29), esophageal (KYSE-150), and triple negative breast cancer (MDA-MB-231) cell lines with EC50s ranging from 0.033-0.092 µM. In vivo, TACH101 triggered effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%. Further evaluation using a panel of patient-derived colorectal models and patient-derived organoids showed a strong correlation of TACH101 sensitivity with MSI-H status (IC50 ranges 1-150 nM). TACH101 also reduced tumorigenic potential by 4.4-fold as determined by FACS analysis using sorted CD44High EpCAM+ population in Limiting Dilution Assays in vivo, suggesting that reduction of cancer stem cells by TACH101 may be effective in therapy-resistant settings. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Extensive preclinical work on TACH101 KDM4 inhibitor shows compelling data and broad applicability as a potential anti-cancer agent. Further evaluation is ongoing to advance the molecule into clinical trials.

ANTITUMOR EFFECT OF SUNITINIB AND BORTEZOMIB ON BREAST CANCER CELL LINE IN VITRO

2017 ◽  
Vol 63 (1) ◽  
pp. 141-145
Author(s):  
Yuliya Khochenkova ◽  
Eliso Solomko ◽  
Oksana Ryabaya ◽  
Yevgeniya Stepanova ◽  
Dmitriy Khochenkov
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Antitumor Effect ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Actual Problem

The discovery for effective combinations of anticancer drugs for treatment for breast cancer is the actual problem in the experimental chemotherapy. In this paper we conducted a study of antitumor effect of the combination of sunitinib and bortezomib against MDA-MB-231 and SKBR-3 breast cancer cell lines in vitro. We found that bortezomib in non-toxic concentrations can potentiate the antitumor activity of sunitinib. MDA-MB-231 cell line has showed great sensitivity to the combination of bortezomib and sunitinib in vitro. Bortezomib and sunitinib caused reduced expression of receptor tyrosine kinases VEGFR1, VEGFR2, PDGFRa, PDGFRß and c-Kit on HER2- and HER2+ breast cancer cell lines

Small Molecular Leads Differentially Active Against HER2 Positive and Triple Negative Breast Cancer Cell Lines

2019 ◽  
Vol 15 (7) ◽  
pp. 738-742 ◽  
Author(s):  
Adnan Badran ◽  
Atia-tul-Wahab ◽  
Sharmeen Fayyaz ◽  
Elias Baydoun ◽  
Muhammad Iqbal Choudhary
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Triple Negative ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Cancer Type

Background:Breast cancer is the most prevalent cancer type in women globally. It is characterized by distinct subtypes depending on different gene expression patterns. Oncogene HER2 is expressed on the surface of cell and is responsible for cell growth regulation. Increase in HER2 receptor protein due to gene amplification, results in aggressive growth, and high metastasis in cancer cells.Methods:The current study evaluates and compares the anti-breast cancer effect of commercially available compounds against HER2 overexpressing BT-474, and triple negative MDA-MB-231 breast cancer cell lines.Results:Preliminary in vitro cell viability assays on these cell lines identified 6 lead molecules active against breast cancer. Convallatoxin (4), a steroidal lactone glycoside, showed the most potent activity with IC50 values of 0.63 ± 0.56, and 0.69 ± 0.59 µM against BT-474 and MDA-MB-231, respectively, whereas 4-[4-(Trifluoromethyl)-phenoxy] phenol (3) a phenol derivative, and Reserpine (5) an indole alkaloid selectively inhibited the growth of BT-474, and MDA-MB-231 breast cancer cells, respectively.Conclusion:These results exhibited the potential of small molecules in the treatment of HER2 amplified and triple negative breast cancers in vitro.

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