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Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress

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Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood–brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20–50 μM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70–100 μM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.
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Molecular and Cellular Biochemistry (2019) 462:195–206
Cytotoxic andantiproliferative eects ofthymoquinone onrat C6
glioma cells depend onoxidative stress
N.G.Krylova1· M.S.Drobysh2· G.N.Semenkova2· T.A.Kulahava1· S.V.Pinchuk3· O.I.Shadyro2
Received: 18 July 2018 / Accepted: 23 February 2019 / Published online: 6 September 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its abil-
ity to cross the blood–brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes.
Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-
dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20–50μM) promoted cell-cycle arrest
and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduc-
tion of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state
of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70–100μM)
induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells
through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action
on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells
to standard chemotherapeutic drugs.
Keywords Glioma· Thymoquinone· Apoptosis· Reactive oxygen species· Mitochondrial dysfunction
Glioblastoma, the highest grade glioma tumor, is the most
common malignant brain tumor [1]. Despite considerable
research efforts, glioblastoma remains incurable because
of its infiltrating growth, quick-developing chemotherapy
resistance and the inability of the majority of anticancer
drugs to penetrate blood–brain barrier. Nowadays, only two
chemotherapeutic agents, namely carmustine and temozo-
lomide, have been approved by the USFDA for treating
malignant gliomas [2, 3]. However, glioma and glioblastoma
often show resistance to these drugs due to a variety of cel-
lular mechanisms that include increased efflux of drugs from
cancer cells, autophagy, cancer stem cells and miRNAs [4,
5]. Therefore, the development of more efficient therapeutic
approaches for the treatment for glioblastoma is required. To
date, naturally occurring phytochemicals which have been
revealed to induce apoptosis of tumor cells are considered
to be one of the most prospective compounds for anticancer
therapy [5].
Quinone derivatives are widely used in medicine as
antibacterial and antiviral agents, antimicotics and chemo-
therapeutic compounds [6]. Doxorubicin, one of the high-
effective anticancer quinones, is used for treatment for
diverse types of tumors such as lymphomas, sarcomas of
various etiology and breast cancer. Natural quinones such as
menadione and thymoquinone (TQ, 2-isopropyl-5-methyl-
1,4-benzoquinone) are considered promising chemothera-
peutic drugs [7, 8]. Antitumor activity of TQ has been dem-
onstrated against different tumors invivo and invitro. TQ
has been shown to cross the blood–brain barrier and induce
Electronic supplementary material The online version of this
article (https :// 0-019-03622 -8) contains
supplementary material, which is available to authorized users.
* T. A. Kulahava
1 Department ofBiophysics, Faculty ofPhysics, Belarusian
State University, 4 Nezavisimosti ave., 220030Minsk,
2 Department ofRadiation Chemistry andPharmaceutical
Technologies, Faculty ofChemistry, Belarusian State
University, 14 Leningradskaya st., 220030Minsk, Belarus
3 Institute ofBiophysics andCell Engineering ofNational
Academy ofSciences ofBelarus, 27 Academicheskaya st.,
220072Minsk, Belarus
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Background: To date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma. Methods: Survival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0. Results: In recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95% CI = 0.26-0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46% of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45%). Severe side effects CTCAE III/IV were observed in 9% of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation. Conclusion: In this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation.
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Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.
Glioblastoma (GBM) is the most common and lethal tumor of the central nervous system. The natural history of treated GBM remains very poor with 5-year survival rates of 5 %. Survival has not significantly improved over the last decades. Currently, the best that can be offered is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. Prognostic factors involved in survival include age, performance status, grade, specific markers (MGMT methylation, mutation of IDH1, IDH2 or TERT, 1p19q codeletion, overexpression of EGFR, etc.) and, likely, the extent of resection. Certain adjuncts to surgery, especially cortical mapping and 5-ALA fluorescence, favor higher rates of gross total resection with apparent positive impact on survival. Recurrent tumors can be offered re-intervention, participation in clinical trials, anti-angiogenic agent or local electric field therapy, without an evident impact on survival. Molecular-targeted therapies, immunotherapy and gene therapy are promising tools currently under research.
Glioblastoma is one of the most fatal and incurable human cancers characterized by nuclear atypia, mitotic activity, intense microvascular proliferation and necrosis. The current standard of care includes maximal safe surgical resection followed by radiation therapy (RT) with concurrent and adjuvant temozolomide (TMZ). The prognosis remains poor with median survival of 14.6 months with RT plus TMZ. Majority will have a recurrence within 2 years from diagnosis despite adequate treatment. Radiosensitizers, radiotherapy dose escalation and altered fractionation have failed to improve outcome. The molecular biology of glioblastoma is complex and poses treatment challenges. High rate of mutation, genotypic and phenotypic heterogeneity, rapid development of resistance, existence of blood-brain barrier (BBB), multiple intracellular and intercellular signalling pathways, over-expression of growth factor receptors, angiogenesis and antigenic diversity renders the tumor cells differentially susceptible to various treatment modalities. Thus, the treatment strategies require personalised or individualized approach based on the characteristics of tumor. Several targeted agents have been evaluated in clinical trials but the results have been modest despite these advancements. This review summarizes the current standard of care, results of concurrent chemoradiation trials, evolving innovative treatments that use targeted therapy with standard chemoradiation or RT alone, outcome of various recent trials and future outlook.
We have recently shown that thymoquinone (TQ) has a potent cytotoxic effect and induces apoptosis via caspase-3 activation with down-regulation of XIAP in mouse neuroblastoma (Neuro-2a) cells. Interestingly, our results showed that TQ was significantly more cytotoxic towards Neuro-2a cells when compared with primary normal neuronal cells. In this study, the effects of TQ on cell-cycle regulation and the mechanisms that contribute to this effect were investigated using Neuro-2a cells. Cell-cycle analysis performed by flow cytometry revealed cell-cycle arrest at G2/M phase and a significant increase in the accumulation of TQ-treated cells at sub-G1 phase, indicating induction of apoptosis by the compound. Moreover, TQ increased the expression of p53, p21 mRNA and protein levels, whereas it decreased the protein expression of PCNA, cyclin B1 and Cdc2 in a dose- dependent manner. Our finding suggests that TQ could suppress cell growth and cell survival via arresting the cell-cycle in the G2/M phase and inducing apoptosis of neuroblastoma cells.