Combined acetyl-11-keto-β-boswellic acid and radiation treatment inhibited glioblastoma tumor cells
| Autor: | Lital Kalich-Philosoph, Yaron Meir, Shahar Lev-Ari, Liat Edry-Botzer, Akiva Vexler, Sylvia Marmor, Natan Shtraus, Gideon Earon, Sefora Conti, Alexander Shtabsky, Lior Hagoel, Benjamin W. Corn |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Treatment lcsh:Medicine Apoptosis chemistry.chemical_compound Mice 0302 clinical medicine Medicine and Health Sciences Blastomas lcsh:Science Neurological Tumors Cultured Tumor Cells Staining Multidisciplinary Radiation medicine.diagnostic_test Cell Death Brain Neoplasms Physics NF-kappa B Cell Staining Combined Modality Therapy Tumor Burden Gene Expression Regulation Neoplastic Platelet Endothelial Cell Adhesion Molecule-1 Proto-Oncogene Proteins c-bcl-2 Oncology Neurology Cell Processes 030220 oncology & carcinogenesis Physical Sciences Boswellic acid Female Biological Cultures medicine.drug Signal Transduction Research Article Clinical Oncology Injections Subcutaneous Glioblastoma Cells Mice Nude Radiation Therapy Research and Analysis Methods Flow cytometry 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans Carcinogen Nuclear Physics Temozolomide business.industry lcsh:R Biology and Life Sciences Cancers and Neoplasms Cell Biology Cell Cultures Antineoplastic Agents Phytogenic Xenograft Model Antitumor Assays Triterpenes Nuclear Staining 030104 developmental biology Ki-67 Antigen chemistry Tumor progression Gamma Rays Specimen Preparation and Treatment Cancer cell Ionizing Radiation Cancer research lcsh:Q Tumor Suppressor Protein p53 Clinical Medicine business Glioblastoma Glioblastoma Multiforme |
| Zdroj: | PLoS ONE, Vol 13, Iss 7, p e0198627 (2018) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Glioblastoma multiforme (GBM) is the most common and most aggressive subtype of malignant gliomas. The current standard of care for newly diagnosed GBM patients involves maximal surgical debulking, followed by radiation therapy and temozolomide chemotherapy. Despite the advances in GBM therapy, its outcome remains poor with a median survival of less than two years. This poor outcome is partly due to the ability of GBM tumors to acquire adaptive resistance to therapy and in particular to radiation. One of the mechanisms contributing to GBM tumor progression and resistance is an aberrant activation of NF-ĸB, a family of inducible transcription factors that play a pivotal role in regulation of many immune, inflammatory and carcinogenic responses. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic terpenoid extracted from the gum Ayurvedic therapeutic plant Boswellia serrata. AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors including GBM. One of the mechanisms underlying AKBA anti-tumor activity is its ability to modulate the NF-ĸB signaling pathway. The present study investigated in vitro and in vivo the effect of combining AKBA with ionizing radiation in the treatment of GBM and assessed AKBA anti-tumor activity and radio-enhancing potential. The effect of AKBA and/or radiation on the survival of cultured glioblastoma cancer cells was evaluated by XTT assay. The mode of interaction of treatments tested was calculated using CalcuSyn software. Inducing of apoptosis following AKBA treatment was evaluated using flow cytometry. The effect of combined treatment on the expression of PARP protein was analysed by Western blot assay. Ectopic (subcutaneous) GBM model in nude mice was used for the evaluation of the effect of combined treatment on tumor growth. Immunohistochemical analysis of formalin-fixed paraffin-embedded tumor sections was used to assess treatment-related changes in Ki-67, CD31, p53, Bcl-2 and NF-ĸB-inhibitor IĸB-α. AKBA treatment was found to inhibit the survival of all four tested cell lines in a dose dependent manner. The combined treatment resulted in a more significant inhibitory effect compared to the effect of treatment with radiation alone. A synergistic effect was detected in some of the tested cell lines. Flow cytometric analysis with Annexin V-FITC/PI double staining of AKBA treated cells indicated induction of apoptosis. AKBA apoptotic activity was also confirmed by PARP cleavage detected by Western blot analysis. The combined treatment suppressed tumor growth in vivo compared to no treatment and each treatment alone. Immunohistochemical analysis showed anti-angiogenic and anti-proliferative activity of AKBA in vivo. It also demonstrated a decrease in p53 nuclear staining and in Bcl-2 staining and an increase in IĸB-α staining following AKBA treatment both alone and in combination with radiotherapy. In this study, we demonstrated that AKBA exerts potent anti-proliferative and apoptotic activity, and significantly inhibits both the survival of glioblastoma cells in vitro and the growth of tumors generated by these cells. Combination of AKBA with radiotherapy was found to inhibit factors which involved in cell death regulation, tumor progression and radioresistence, therefore it may serve as a novel approach for GBM patients. |
| Databáze: | OpenAIRE |
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