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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. New triorganotin( iv ) compounds with aromatic carboxylate ligands: synthesis and evaluation of the pro-apoptotic mechanism

   https://doi.org/10.1039/D0RA06695H  

   Rashid, Faisal ; Uddin, Noor ; Ali, Saqib ; Haider, Ali ; Tirmizi, Syed Ahmad ; Diaconescu, Paula L. ; Iqbal, Jamshed ( January 2021 , RSC Advances)

   Three new organotin( iv ) carboxylate compounds were synthesized and structurally characterized by elemental analysis and FT-IR and multinuclear NMR ( 1 H, 13 C, 119 Sn) spectroscopy. Single X-ray crystallography reveals that compound C2 has a monoclinic crystal system with space group P 2 1 / c having distorted bipyramidal geometry defined by C 3 SnO 2 . The synthesized compounds were screened for drug-DNA interactions via UV-Vis spectroscopy and cyclic voltammetry showing good activity with high binding constants. Theoretical investigations also support the reactivity of the compounds as depicted from natural bond orbital (NBO) analysis using Gaussian 09. Synthesized compounds were initially evaluated on two cancer (HeLa and MCF-7) cell lines and cytotoxicity to normal cells was evaluated using a non-cancerous (BHK-21) cell line. All the compounds were found to be active, with IC 50 values less than that of the standard drug i.e. cisplatin. The cytotoxic effect of the most potent compound C2 was confirmed by LDH cytotoxicity assay and fluorescence imaging after PI staining. Apoptotic features in compound C2 treated cancer cells were visualized after DAPI staining while regulation of apoptosis was observed by reactive oxygen species generation, binding of C2 with DNA, a change in mitochondrial membrane potential and expression of activated caspase-9 and caspase-3 in cancer cells. Results are indicative of activation of the intrinsic pathway of apoptosis in C2 treated cancer cells. 

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4. Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death

   https://doi.org/10.3390/cancers11030357  

   Sansalone, Lorenzo ; Veliz, Eduardo ; Myrthil, Nadia ; Stathias, Vasileios ; Walters, Winston ; Torrens, Ingrid ; Schürer, Stephan ; Vanni, Steven ; Leblanc, Roger ; Graham, Regina ( March 2019 , Cancers)

   Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target. 

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5. 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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