Enhancing temozolomide antiglioma response by inhibiting O6-methylguanine-DNA methyltransferase with selected phytochemicals: in silico and in vitro approach.

The aim of our study was to investigate the potential of rutin, catechin, dehydrozingerone, naringenin, and quercetin, both alone and in combination with temozolomide, to inhibit the expression of O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. MGMT has been shown to be a major cause of temozolomide resistance in glioma. Our study used both in silico and in vitro methods to assess the inhibitory activity of these phytochemicals on MGMT, with the goal of identifying the most effective combination of compounds for reducing temozolomide resistance. After conducting an initial in silico screening of natural compounds against MGMT protein, five phytochemicals were chosen based on their high docking scores and favorable binding energies. From the molecular docking and simulation studies, we found that quercetin showed a good inhibitory effect of MGMT with its high binding affinity. C6 glioma cells showed increased cytotoxicity when treated with the temozolomide and quercetin combination. It was understood from the isobologram and combination index plot that the drug combination showed a synergistic effect at the lowest dose. Quercetin when combined with temozolomide significantly decreased the MGMT levels in C6 cells in comparison with the other drugs as estimated by ELISA. The percentage of apoptotic cells increased significantly in the temozolomide-quercetin group indicating the potency of quercetin in decreasing the resistance of temozolomide as confirmed by acridine orange/ethidium bromide staining. Our experiment hence suggests that temozolomide resistance can be reduced by combining the drug with quercetin which will serve as an effective therapeutic target for glioblastoma treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03821-7.

Temozolomide Resistance: A Multifarious Review on Mechanisms Beyond O-6-Methylguanine-DNA Methyltransferase.

BACKGROUND: Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the impoverished prognosis and sparse chemotherapeutic medicaments associated with glioblastoma, the burgeoning resistance to temozolomide has made the whole condition almost irremediable. OBJECTIVE: The present review highlights the possible mechanisms of drug resistance following chemotherapy with temozolomide. METHODS: The review summarizes the recent developments, as published in articles from Scopus, PubMed, and Web of Science search engines. DESCRIPTION: One of the prime resistance mediators, O-6-methylguanine-DNA methyltransferase, upon activation, removes temozolomide-induced methyl adducts bound to DNA and reinstates genomic integrity. In the bargain, neoteric advances in the conception of temozolomide resistance have opened the door to explore several potential mediators like indirect DNA repair systems, efflux mechanisms, epigenetic modulation, microenvironmental influences, and autophagy-apoptosis processes that constantly lead to the failure of chemotherapy. CONCLUSION: This review sheds light on recent discoveries, proposed theories, and clinical developments in the field of temozolomide resistance to summarize the complex and intriguing involvement of oncobiological pathways.

Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases.

Exosomes are extracellular vesicles with the diameter ranging from 50 to 100 nm and are found in different body fluids such as blood, cerebrospinal fluid (CSF), urine and saliva. Like in case of various diseases, based on the parent cells, the content of exosomes (protein, mRNA, miRNA, DNA, lipids and metabolites) varies and thus can be utilized as potential biomarker for diagnosis and prognosis of the brain diseases. Furthermore, utilizing the natural potential exosomes to cross the blood-brain barrier and by specifically decorating it with the ligand as per the desired brain sites therapeutics can be delivered to brain parenchyma. This review article conveys the importance of exosomes and their use in the treatment and diagnosis of brain/central nervous system diseases.

Dehydrozingerone protects temozolomide-induced cognitive impairment in normal and C6 glioma rats besides enhancing its anticancer potential.

Considering the cognitive impairment induced by temozolomide (TMZ) in glioblastoma survivors, the present study was aimed to evaluate the protective effect of dehydrozingerone (DHZ) against TMZ-induced cognitive impairment (chemobrain) and C6 cell line-induced glioma in male Wistar rats. In both chemobrain and glioma models, TMZ was administered at a dose of 18 mg/kg i.v every 5th day and DHZ at a dose of 100 mg/kg p.o. daily. Additionally, glioma was induced by intracerebral injection of 5 × 104 C6 rat glioma cells in the cortex in the glioma model. Upon disease induction and treatment with TMZ + DHZ, spatial memory was assessed by the Morris water maze (MWM) test and episodic memory by the novel object recognition test (NORT). The induction of glioma was confirmed by histology of the cortex. Hippocampus and frontal cortex were subjected to antioxidant evaluation. Significant loss of spatial and episodic memory was observed with TMZ treatment which was significantly restored by DHZ. DHZ showed significant improvement in oxidative stress markers reversed the histopathological features in the cortex. TMZ-induced elevation of the glutathione level was also reversed by DHZ, indicating the role of DHZ in the reversal of TMZ resistance. In the glioma model, the improvement in cognition by DHZ correlated with the decrease in tumor volume. Altogether, the study results reveal the role of TMZ in worsening the memory and DHZ in reversing it, besides, improving its anticancer potential.