ArticlePublisher preview available
To read the full-text of this research, you can request a copy directly from the authors.

Abstract and Figures

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.
This content is subject to copyright. Terms and conditions apply.
1 3
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... It was observed that the development of cytosolic ROS in glioma cells was increased at a concentration of TQ greater than 20 μM. Maximum iROS production has been detected at 50-70 μM TQ in cells [47]. In our study, we showed that TQ increases iROS generation on glioma cells; therefore, it affects cell viability and apoptosis. ...
... Thus, pro-oxidant agents such as TQ can be considered a viable way to selectively induce cancer cell death while protecting normal cells. To date, several intracellular iROS modulating and GSH-reducing agents have demonstrated anti-tumor activity in preclinical and clinical studies [47,51]. From our obtained results of GSH, it is observed that TQ also decreases the GSH levels on C6 glioma cells in comparison to the control. ...
Full-text available
Glioblastoma, as an invasive tumor, is one of the most common primary malignant brain tumors. Despite maximum aggressive treatment, patients with glioblastoma have a dismal prognosis. Thymoquinone (TQ) has been found to show anti-cancer effects on different types of cancer. There are a few in vitro studies on the effect of TQ on glial tumors. However, the molecular mechanism of TQ's anti-cancer effect has not been fully elucidated. In the present study, we aimed to investigate the genotoxic, apoptotic, and cytotoxic effects of TQ on C6 rat glioma cells. C6 glioma cells were analyzed after 24 h of exposure to different concentrations of TQ by the ATP cell viability assay for cytotoxicity, comet assay for genotoxicity, 2′,7′dichlorodihydrofluorescein diacetate (H2DCF-DA) for intracellular reactive oxygen species (iROS) generation, 3.3′dihexyloxacarbocyanine iodide (DiOC6(3)) for mitochondrial membrane potential, GSH/GSSG-Glo Assay for glutathione level and Fura-2AM for intracellular calcium levels. Apoptosis induction was studied by acridine orange/ethidium bromide double staining, flow cytometry, and western blotting analyses. Caspase-3, Caspase-9, Bax, Bcl-2, and pSTAT3 protein levels were determined by the western blotting method. Cytotoxicity was enhanced by TQ in C6 glioma cells in a concentration-dependent manner. TQ also induced DNA damage, apoptosis, and increased iROS. Also, MMP and GSH levels were decreased by TQ. It inhibited pSTAT3, resulting in apoptosis induction through the regulation of anti-apoptotic and pro-apoptotic proteins. Our results suggest that TQ would be an effective treatment in glioma. Further studies should support these findings.
... Proteins. It is known that intracellular oxidative stress can modulate redox-dependent Akt and mitogen-activated protein kinase (MAPK) signal transduction pathways, which can lead to apoptosis of cancer cells [80]. The p38 mitogen-activated protein kinase is a member of MAPK family proteins and supports a key role in mediating resistance to anticancer treatments, also promoting cell growth, survival signaling, proliferation, migration, and inflammation [81]. ...
Full-text available
Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment options are still lacking. Imidazo[1,2-a]pyridine derivatives and organoselenium compounds are largely used in medicinal chemistry and drug development. This study is aimed at further investigating the antitumor mechanism of IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine), a selenylated imidazo[1,2-a]pyridine derivative in glioblastoma cells. IP-Se-06 exhibited high cytotoxicity against A172 cells ( I C 50 = 1.8 μ M ) and selectivity for this glioblastoma cell. The IP-Se-06 compound has pharmacological properties verified in its ADMET profile, especially related to blood-brain barrier (BBB) permeability. At low concentration (1 μM), IP-Se-06 induced intracellular redox state modulation with depletion of TrxR and GSH levels as well as inhibition of NRF2 protein. IP-Se-06 also decreased mitochondrial membrane potential, induced cytochrome c release, and chromatin condensation. Furthermore, IP-Se-06 induced apoptosis by decreasing levels of Bcl-xL while increasing levels of γ-H2AX and p53 proteins. Treatment with IP-Se-06 induced cell cycle arrest and showed antiproliferative effect by inhibition of Akt/mTOR/HIF-1α and ERK 1/2 signaling pathways. In addition, IP-Se-06 displayed significant inhibition of p38 MAPK and p-p38, leading to inhibition of inflammasome complex proteins (NLRP3 and caspase-1) in glioblastoma cells. These collective findings demonstrated that IP-Se-06 is a bioactive molecule that can be considered a candidate for the development of a novel drug for glioblastoma treatment.
... Regarding gliomas, early assays in U87MG and T98G cell lines showed that increasing amounts of thymoquinone resulted in significant alterations in cell morphology and impaired viability in a dose-dependent and time-dependent manner in both cell lines, although the wild-type TP53 cell line was more sensitive [395]. DNA damage, cell cycle arrest, inhibition of colony formation, ROS generation, apoptosis induction, and migration impairment were also observed by others [396][397][398][399][400][401]. In most cases, without affecting normal cells [402,403]. ...
Full-text available
Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.
... This triggers the intrinsic pathway and activates procaspases 9, 7, 3 and PARP enzyme cleavage. This cascade of events is seen in leukemia/lymphoma [88,89], glioblastoma [79,90], renal cell carcinoma [91], colon [92], brain [93], bladder [84] and ovarian cancers [82]. TQ has been reported to exert a dual effect in which it acts as both pro-oxidant and antioxidant in a dose-dependent manner; the antioxidant effect occurs at low concentration (<5 µM) whereas, at higher concentrations (>20 µM), it possesses prooxidant property [94]. ...
Full-text available
Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-2) pandemic, arace to develop a vaccine has been initiated, considering the massive and rather significant economic and healthcare hits that this virus has caused. The pathophysiology occurring following COVID-19(coronavirus disease-2019) infection has givenhints regarding the supportive and symptomatic treatments to establish for patients, as no specific anti-SARS-CoV-2 is available yet. Patient symptoms vary greatly and range from mild symptoms to severe fatal complications. Supportive treatments include antipyretics, antiviral therapies, different combinations of broad-spectrum antibiotics, hydroxychloroquine and plasma transfusion. Unfortunately, cancer patients are at higher risk of viral infection and more likely to develop serious complications due to their immunocompromised state, the fact that they are already administering multiple medications, as well as combined comorbidity compared to the general population. It may seem impossible to find a drug that possesses both potent antiviral and anticancer effects specifically against COVID-19 infection and its complications and the existing malignancy, respectively. Thymoquinone (TQ) is the most pharmacologically active ingredient in Nigella sativa seeds (black seeds); it is reported to have anticancer, anti-inflammatory and antioxidant effects in various settings. In this review, we will discuss the multiple effects of TQ specifically against COVID-19, its beneficial effects against COVID-19 pathophysiology and multiple-organ complications, its use as an adjuvant for supportive COVID-19 therapy and cancer therapy, and finally, its anticancer effects.
... Extracts of medicinal plants have beneficial effects in experimental models both in vivo (Rezvani et al., 2010 for V. officinalis, andIlesanmi et al., 2019 for Antiaris africana) and in vitro (Areiza-Mazo et al., 2018 for Physalis peruviana). Therefore, in addition to the CSD model, we analyzed the V. officinalis/rotenone interaction in a set of in vitro experiments in the rat C6 glioma cell culture model (Grobben et al., 2002;Krylova et al., 2019). Rat C6 glioma cells have been used to study the effects of valproic acid as an inhibitor of histone deacetylase (Ximenes et al., 2012). ...
Full-text available
Astrocytes can protect neurons against oxidative stress and excitability-dependent disorders, such as epilepsy. Valeriana officinalis has been used as anticonvulsant and can exert an antioxidant effect, which may underlie its opposing action against the toxic effects of the pesticide rotenone. We investigated the V. officinalis/rotenone interaction in the cortical spreading depression (CSD), a phenomenon that depends upon brain excitability (in vivo model). In addition, we analyzed the protective action of V. officinalis against the cytotoxic effects of rotenone in cultures of rat C6 glioma cells (in vitro model). For the CSD study, Wistar rats received either V. officinalis (250 mg/kg/day via gavage for 15 days; n = 8) or 10 mg/kg/day rotenone via subcutaneous injections for 7 days (n = 7), or they received both substances (n = 5). Two control groups received either saline (vehicle for V. officinalis; n = 8) or 1% Tween-80 aqueous solution (vehicle for rotenone; n = 9). After treatment, CSD was recorded for 4 h. The rotenone- and V. officinalis-treated groups presented, respectively, with lower (2.96 ± 0.14 mm/min), and higher CSD propagation velocity (3.81 ± 0.10 mm/min) when compared with the controls (Tween-80, 3.37 ± 0.06 mm/min and saline, 3.35 ± 0.08 mm/min; p < 0.05). The rotenone plus V. officinalis-treated group displayed a CSD velocity (3.38 ± 0.07 mm/min) that was similar to controls. In line with these results, in vitro experiments on rat glioma C6 cells revealed a protective effect (MTT assay) of V. officinalis against rotenone-induced cytotoxicity. These results suggest the therapeutic potential of V. officinalis for treating neurological diseases involving redox imbalance and astrocyte dysfunction.
Full-text available
Despite great advances, therapeutic approaches of osteosarcoma, the most prevalent class of preliminary pediatric bone tumors, as well as bone-related malignancies, continue to demonstrate insufficient adequacy. In recent years, a growing trend toward applying natural bioactive compounds, particularly phytochemicals, as novel agents for cancer treatment has been observed. Bioactive phytochemicals exert their anticancer features through two main ways: they induce cytotoxic effects against cancerous cells without having any detrimental impact on normal cell macromolecules such as DNA and enzymes, while at the same time combating the oncogenic signaling axis activated in tumor cells. Thymoquinone (TQ), the most abundant bioactive compound of Nigella sativa , has received considerable attention in cancer treatment owing to its distinctive properties, including apoptosis induction, cell cycle arrest, angiogenesis and metastasis inhibition, and reactive oxygen species (ROS) generation, along with inducing immune system responses and reducing side effects of traditional chemotherapeutic drugs. The present review is focused on the characteristics and mechanisms by which TQ exerts its cytotoxic effects on bone malignancies.
Full-text available
Thymoquinone (TQ) is a bioactive molecule with anticancer as well as anti-inflammatory activities via the downregulation of several chemokines and cytokines. Administering it as a nanoformulation increases its therapeutic value. As per the WHO, approximately 80% of the global population utilizes indigenous systems of medicine for their primary health care . Recently, various potential phytocandidates such as β-elemene, brazilin, bufalin, cardamonin, cryptotanshinone, isogarcinol, curcumin, celastrol, lapachol, nobiletin, oroxylin A, thymoquinone, resveratrol, torilin, and swertiamarin have been identified to have pharmacological properties [1]. Thymoquinone (TQ) is a crucial active ingredient obtained from the black seed of the plant Nigella sativa (NS) and Caram carvil, with potential antioxidant and anti-inflammatory activities [2][3]. It holds a wide range of other therapeutic properties, including hepatoprotective, cardioprotective, anticancer, antidiabetic, and antimicrobial properties [4]. Moreover, TQ also nullifies oxidative stress and prevents any damage to the tissue or cellular environment [5]
Full-text available
Cancer causes a considerable amount of mortality in the world, while arthritis is an im-munological dysregulation with multifactorial pathogenesis including genetic and environmental defects. Both conditions have inflammation as a part of their pathogenesis. Resistance to anticancer and disease-modifying antirheumatic drugs (DMARDs) happens frequently through the generation of energy-dependent transporters, which lead to the expulsion of cellular drug contents. Thymoqui-none (TQ) is a bioactive molecule with anticancer as well as anti-inflammatory activities via the downregulation of several chemokines and cytokines. Nevertheless, the pharmacological importance and therapeutic feasibility of thymoquinone are underutilized due to intrinsic pharmaco-kinetics, including short half-life, inadequate biological stability, poor aqueous solubility, and low bioavailability. Owing to these pharmacokinetic limitations of TQ, nanoformulations have gained remarkable attention in recent years. Therefore, this compilation intends to critically analyze recent advancements in rheumatoid arthritis and cancer delivery of TQ. This literature search revealed that nanocarriers exhibit potential results in achieving targetability, maximizing drug internaliza-tion, as well as enhancing the anti-inflammatory and anticancer efficacy of TQ. Additionally, TQ-NPs (thymoquinone nanoparticles) as a therapeutic payload modulated autophagy as well as enhanced the potential of other drugs when given in combination. Moreover, nanoformulations improved pharmacokinetics, drug deposition, using EPR (enhanced permeability and retention) and receptor-mediated delivery, and enhanced anti-inflammatory and anticancer properties. TQ's potential to reduce metal toxicity, its clinical trials and patents have also been discussed.
Full-text available
Thymoquinone (TQ) is a bioactive component derived from the seeds of Nigella sativa that are commonly as black cumin. Evidences indicate that the medicinal properties of TQ have been recognized for more than 2000 years. TQ has been shown to possess potent chemopreventive properties that include anti-inflammatory and anti-neoplastic activities. Recent studies have unraveled the multiple mechanisms through which TQ exerts its chemopreventive and anticancer activity in different cancer cells in a contextual manner. The present review aims to provide a brief compendium on the molecular mechanisms through which TQ inhibits signaling pathways underlying cancer genesis, progression, and metastasis.
Four novel indole steroids based on dehydroepiandrosterone (IS-1), estrone (IS-2) and pregnenolone (IS-3) were obtained and studied for their ability to inhibit C6 glioma proliferation. A reduction in cell proliferation by 52±13% was observed for IS-1 at 10 μM, whereas IS-3 and abiraterone acetate at 10 μM caused a 36±8% decrease. Surprisingly, the cellular effects reported for abiraterone, namely, cytochrome P450 CYP17A1 inhibition and endoplasmic reticulum stress were not detected for IS-1. However, both abiraterone and IS-1 significantly increased glutathione levels. Docking studies predicted good affinity of IS-1 to liver X receptors and regulatory protein Keap1, which are proposed to be involved in the compounds' antiproliferative activity.
Full-text available
The effect of coenzyme Q10 on glioma-cell proliferation under serum-deprived conditions has been studied. Our results have shown that the addition of coenzyme Q10 into a serum-free culture medium enhances cell viability, stimulates cell growth, restores mitochondrial potential, and increases the quantity of energized mitochondria. It is found that coenzyme Q10-induced glioma-cell proliferation in conditions of serum deficiency is a result of an intracellular reduced glutathione concentration with subsequent activation of protein kinase C, ERK1/2, and phosphoinositol-3-kinase.
Full-text available
Objective(s) Glioblastoma multiforme (GBM) is one of the most lethal forms of human cancer and temozolomide (TMZ) is currently part of the standard treatment for this disease. Combination therapy using natural substances can enhance the anti-cancer activity of TMZ. The purpose of this study was to evaluate the effect of TMZ in combination with thymoquinone (TQ) on human GBM cell line (U87MG). Materials and Methods The cell line was treated with TMZ and/or TQ. Cell viability was assessed using trypan blue and MTT assay. The effect of TMZ and/or TQ on colony-forming ability of the cells was investigated. Apoptosis and autophagy were quantified by fluorescent dye staining. The expression level of two autophagy related genes (ATG) were assessed using RT-PCR. Furthermore, nitric oxide (NO) production was detected by Griess reaction. Results After treatment with TMZ and/or TQ, the cell viability was reduced in a time- and dose-dependent manner, and the cell survival fraction (SF) was significantly decreased (P=0.000). Apoptosis index of U87MG cells was also significantly increased (P=0.000). Autophagy was significantly increased by TMZ (P=0.000) and decreased by TQ (P=0.018). Also TMZ and/or TQ significantly decreased NO production by U87MG cell (P=0.000). Conclusion TQ enhanced the anti-cancer activity of TMZ by inhibition of autophagy at the transcriptional level and decreased the colony-forming ability and NO production of U87MG cell line.
Full-text available
Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas.
Full-text available
Background: Nigella sativa has been a nutritional flavoring factor and natural treatment for many ailments for so many years in medical science. Earlier studies have been reported that thymoquinone (TQ), an active compound of its seed, contains anticancer properties. Previous studies have shown that TQ induces apoptosis in breast cancer cells but it is unclear the role of P53 in the apoptotic pathway. Hereby, this study reports the potency of TQ on expression of tumor suppressor gene P53 and apoptosis induction in breast cancer cell line Michigan Cancer Foundation-7 (MCF-7). Methods: MCF-7 cell line was cultured and treated with TQ, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out for evaluating the half-maximal inhibitory concentration (IC50) values after 24 h of treatment. The percentage of apoptotic cells was measured by flow cytometry. Real-time polymerase chain reaction (PCR) was performed to estimate the messenger RNA expression of P53 in MCF-7 cell line at different times. Results: The IC50 value for the TQ in MCF-7 cells was 25 μM that determined using MTT assay. The flow cytometry and real-time PCR results showed that TQ could induce apoptosis in MCF-7 cells, and the P53 gene expression was dramatically up-regulated by ascending time, respectively. Hence, there was significant difference in 48 and 72 h. Conclusions: Our results demonstrated that TQ could induce apoptosis in MCF-7 cells through up-regulation of P53 expression in breast cancer cell line (MCF-7) by time-dependent manner.
Full-text available
Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.
Full-text available
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.
Full-text available
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.