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1. In Vitro and In Vivo Enhancement of Temozolomide Effect in Human Glioblastoma by Non-Invasive Application of Cold Atmospheric Plasma

   https://doi.org/10.3390/cancers13174485  

   Soni, Vikas ; Adhikari, Manish ; Simonyan, Hayk ; Lin, Li ; Sherman, Jonathan H. ; Young, Colin N. ; Keidar, Michael ( September 2021 , Cancers)

   null (Ed.)

   Glioblastoma (GBM) is one of the most aggressive forms of adult brain cancers and is highly resistant to treatment, with a median survival of 12–18 months after diagnosis. The poor survival is due to its infiltrative pattern of invasion into the normal brain parenchyma, the diffuse nature of its growth, and its ability to quickly grow, spread, and relapse. Temozolomide is a well-known FDA-approved alkylating chemotherapy agent used for the treatment of high-grade malignant gliomas, and it has been shown to improve overall survival. However, in most cases, the tumor relapses. In recent years, CAP has been used as an emerging technology for cancer therapy. The purpose of this study was to implement a combination therapy of CAP and TMZ to enhance the effect of TMZ and apparently sensitize GBMs. In vitro evaluations in TMZ-sensitive and resistant GBM cell lines established a CAP chemotherapy enhancement and potential sensitization effect across various ranges of CAP jet application. This was further supported with in vivo findings demonstrating that a single CAP jet applied non-invasively through the skull potentially sensitizes GBM to subsequent treatment with TMZ. Gene functional enrichment analysis further demonstrated that co-treatment with CAP and TMZ resulted in a downregulation of cell cycle pathway genes. These observations indicate that CAP can be potentially useful in sensitizing GBM to chemotherapy and for the treatment of glioblastoma as a non-invasive translational therapy. 

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2. Combination therapy of cold atmospheric plasma (CAP) with temozolomide in the treatment of U87MG glioblastoma cells

   https://doi.org/10.1038/s41598-020-73457-7  

   Gjika, Eda ; Pal-Ghosh, Sonali ; Kirschner, Megan E. ; Lin, Li ; Sherman, Jonathan H. ; Stepp, Mary Ann ; Keidar, Michael ( October 2020 , Scientific Reports)

   Cold atmospheric plasma (CAP) technology, a relatively novel technique mainly investigated as a stand-alone cancer treatment method in vivo and in vitro, is being proposed for application in conjunction with chemotherapy. In this study, we explore whether CAP, an ionized gas produced in laboratory settings and that operates at near room temperature, can enhance Temozolomide (TMZ) cytotoxicity on a glioblastoma cell line (U87MG). Temozolomide is the first line of treatment for glioblastoma, one of the most aggressive brain tumors that remains incurable despite advancements with treatment modalities. The cellular response to a single CAP treatment followed by three treatments with TMZ was monitored with a cell viability assay. According to the cell viability results, CAP treatment successfully augmented the effect of a cytotoxic TMZ dose (50 μM) and further restored the effect of a non-cytotoxic TMZ dose (10 μM). Application of CAP in conjunction TMZ increased DNA damage measured by the phosphorylation of H2AX and induced G2/M cell cycle arrest. These findings were supported by additional data indicating reduced cell migration and increased αvβ3 and αvβ5 cell surface integrin expression as a result of combined CAP–TMZ treatment. The data presented in this study serve as evidence that CAP technology can be a suitable candidate for combination therapy with existing chemotherapeutic drugs. CAP can also be investigated in future studies for sensitizing glioblastoma cells to TMZ and other drugs available in the market.

    

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3. Kalata B1 Enhances Temozolomide Toxicity to Glioblastoma Cells

   https://doi.org/10.3390/biomedicines12102216  

   Gerlach, Samantha L ; Metcalf, James S ; Dunlop, Rachael A ; Banack, Sandra Anne ; Her, Cheenou ; Krishnan, Viswanathan V ; Göransson, Ulf ; Gunasekera, Sunithi ; Slazak, Blazej ; Cox, Paul Alan ( October 2024 , Biomedicines)

   Glioblastoma (GBM) is the most aggressive cancer originating in the brain, but unfortunately combination treatments with resection, radiation, and chemotherapy are relatively ineffective. Therefore, novel methods of adjuvant therapy are critically needed. Cyclotides are plant-derived circular peptides that chemosensitize drug-resistant breast cancer to doxorubicin. We analyzed naturally occurring and synthetic cyclotides (Cycloviolacin O3, Cycloviolacin O19, natural Kalata B1, synthetic Kalata B1, and Vitri E) alone and in co-exposure treatments with the drug temozolomide (TMZ) in human glioblastoma cells. The cyclotides were identified by UPLC-PDA and HPLC-UV. The synthetic Kalata B1 sequence was verified with orbitrap LC-MS, and structural confirmation was provided by NMR spectroscopy. The cyclotides displayed dose-dependent cytotoxicity (IC50 values 2.4–21.1 µM) both alone and as chemosensitizers of U-87 MG and T 98 cells to TMZ. In fact, a 16-fold lower concentration of TMZ (100 µM) was needed for significant cytotoxicity in U-87 MG cells co-exposed to synthetic Kalata B (0.5 µM). Similarly, a 15-fold lower concentration of TMZ (75 µM) was required for a significant reduction in cell viability in T 98 cells co-exposed to synthetic Kalata B1 (0.25 µM). Kalata B1 remained stable in human serum stability assays. The data support the assertion that cyclotides may chemosensitize glioblastoma cells to TMZ.

    

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4. The anti-glioblastoma effect of cold atmospheric plasma treatment: physical pathway v.s. chemical pathway

   https://doi.org/10.1038/s41598-020-68585-z  

   Yan, Dayun ; Wang, Qihui ; Malyavko, Alisa ; Zolotukhin, Denis B. ; Adhikari, Manish ; Sherman, Jonathan H. ; Keidar, Michael ( July 2020 , Scientific Reports)

   Cold atmospheric plasma (CAP), a near room temperature ionized gas, has shown potential application in many branches of medicine, particularly in cancer treatment. In previous studies, the biological effect of CAP on cancer cells and other mammalian cells has been based solely on the chemical factors in CAP, particularly the reactive species. Therefore, plasma medicine has been regarded as a reactive species-based medicine, and the physical factors in CAP such as the thermal effect, ultraviolet irradiation, and electromagnetic effect have been regarded as ignorable factors. In this study, we investigated the effect of a physical CAP treatment on glioblastoma cells. For the first time, we demonstrated that the physical factors in CAP could reinstate the positive selectivity on CAP-treated astrocytes. The positive selectivity was a result of necrosis, a new cell death in glioblastoma cells characterized by the leak of bulk water from the cell membrane. The physically-based CAP treatment overcomed a large limitation of the traditional chemically based CAP treatment, which had complete dependence on the sensitivity of cells to reactive species. The physically-based CAP treatment is a potential non-invasive anti-tumor tool, which may have wide application for tumors located in deeper tissues.

    

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5. Drug target ranking for glioblastoma multiforme

   https://doi.org/10.1186/s42490-021-00052-w  

   Saraf, Radhika ; Agah, Shaghayegh ; Datta, Aniruddha ; Jiang, Xiaoqian ( April 2021 , BMC Biomedical Engineering)

   Glioblastoma Multiforme, an aggressive primary brain tumor, has a poor prognosis and no effective standard of care treatments. Most patients undergoing radiotherapy, along with Temozolomide chemotherapy, develop resistance to the drug, and recurrence of the tumor is a common issue after the treatment. We propose to model the pathways active in Glioblastoma using Boolean network techniques. The network captures the genetic interactions and possible mutations that are involved in the development of the brain tumor. The model is used to predict the theoretical efficacies of drugs for the treatment of cancer.

   We use the Boolean network to rank the critical intervention points in the pathway to predict an effective therapeutic strategy for Glioblastoma. Drug repurposing helps to identify non-cancer drugs that could be effective in cancer treatment. We predict the effectiveness of drug combinations of anti-cancer and non-cancer drugs for Glioblastoma.

   Given the genetic profile of a GBM tumor, the Boolean model can predict the most effective targets for treatment. We also identified two-drug combinations that could be more effective in killing GBM cells than conventional chemotherapeutic agents. The non-cancer drug Aspirin could potentially increase the cytotoxicity of TMZ in GBM patients.

    

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