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SNAP reverses temozolomide resistance in human glioblastoma multiforme cells through down-regulation of MGMT. 2019

Chia-Kuang Tsai, and Li-Chun Huang, and Yi-Ping Wu, and I-Ying Kan, and Dueng-Yuan Hueng
Department of Neurology, Tri-Service General Hospital, Taipei, Taiwan.

Glioblastoma multiforme (GBM) is the most frequently occurring and gravest primary tumor of the CNS in adults. The development of chemoresistance to temozolomide (TMZ), the first-line chemotherapy for GBM, is an important factor contributing to poor treatment outcomes. Down-regulation of O-6-methylguanine-DNA methyltransferase (MGMT) expression in GBM cells is an attractive strategy for overcoming TMZ resistance and improving outcomes. This study revealed that the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) exerts antitumorigenic effects on TMZ-sensitive and TMZ-resistant (TMZ-R) glioma cells. Pretreatment with SNAP not only induced apoptosis, mitochondrial dysfunction, and hypoxia-inducing factor 1, but also resensitized TMZ-R GBM cells to TMZ through down-regulation of MGMT expression. SNAP acted principally through post-translational modification of p53, phosphorylated N-myc downstream regulated gene 1, and MGMT protein stability in TMZ-R GBM cells. Additionally, when applied together, SNAP and TMZ enhanced the inhibition of tumor growth in vitro and in vivo. This study sheds new light on a potential strategy to overcome TMZ resistance in GBM and thus possesses the potential for prolonging survival of patients with GBM.-Tsai, C.-K., Huang, L.-C., Wu, Y.-P., Kan, I.-Y., Hueng, D.-Y. SNAP reverses temozolomide resistance in human glioblastoma multiforme cells through down-regulation of MGMT.

UI MeSH Term Description Entries
D008819 Mice, Nude Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses. Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D009374 Neoplasms, Experimental Experimentally induced new abnormal growth of TISSUES in animals to provide models for studying human neoplasms. Experimental Neoplasms,Experimental Neoplasm,Neoplasm, Experimental
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005909 Glioblastoma A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. They may arise in any region of the central nervous system, with a predilection for the cerebral hemispheres, basal ganglia, and commissural pathways. Clinical presentation most frequently occurs in the fifth or sixth decade of life with focal neurologic signs or seizures. Astrocytoma, Grade IV,Giant Cell Glioblastoma,Glioblastoma Multiforme,Astrocytomas, Grade IV,Giant Cell Glioblastomas,Glioblastoma, Giant Cell,Glioblastomas,Glioblastomas, Giant Cell,Grade IV Astrocytoma,Grade IV Astrocytomas
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077204 Temozolomide A dacarbazine derivative that is used as an alkylating antineoplastic agent for the treatment of MALIGNANT GLIOMA and MALIGNANT MELANOMA. 8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one,CCRG 81045,CCRG-81045,M&B 39831,M&B-39831,Methazolastone,NSC 362856,NSC-362856,TMZ-Bioshuttle,TMZA-HE,Temodal,Temodar,Temozolomide Hexyl Ester,CCRG81045,M&B39831,NSC362856,TMZ Bioshuttle
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015254 DNA Modification Methylases Enzymes that are part of the restriction-modification systems. They are responsible for producing a species-characteristic methylation pattern, on either adenine or cytosine residues, in a specific short base sequence in the host cell's own DNA. This methylated sequence will occur many times in the host-cell DNA and remain intact for the lifetime of the cell. Any DNA from another species which gains entry into a living cell and lacks the characteristic methylation pattern will be recognized by the restriction endonucleases of similar specificity and destroyed by cleavage. Most have been studied in bacterial systems, but a few have been found in eukaryotic organisms. DNA Modification Methyltransferases,Modification Methylases,Methylases, DNA Modification,Methylases, Modification,Methyltransferases, DNA Modification,Modification Methylases, DNA,Modification Methyltransferases, DNA
D015415 Biomarkers Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc. Biochemical Markers,Biological Markers,Biomarker,Clinical Markers,Immunologic Markers,Laboratory Markers,Markers, Biochemical,Markers, Biological,Markers, Clinical,Markers, Immunologic,Markers, Laboratory,Markers, Serum,Markers, Surrogate,Markers, Viral,Serum Markers,Surrogate Markers,Viral Markers,Biochemical Marker,Biologic Marker,Biologic Markers,Clinical Marker,Immune Marker,Immune Markers,Immunologic Marker,Laboratory Marker,Marker, Biochemical,Marker, Biological,Marker, Clinical,Marker, Immunologic,Marker, Laboratory,Marker, Serum,Marker, Surrogate,Serum Marker,Surrogate End Point,Surrogate End Points,Surrogate Endpoint,Surrogate Endpoints,Surrogate Marker,Viral Marker,Biological Marker,End Point, Surrogate,End Points, Surrogate,Endpoint, Surrogate,Endpoints, Surrogate,Marker, Biologic,Marker, Immune,Marker, Viral,Markers, Biologic,Markers, Immune

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