Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27

Sang, Dong-ping; Li, Ru-jun; Lan, Qing

doi:10.1038/aps.2014.22

Cited by 82 publications

(42 citation statements)

References 22 publications

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“…8). A recent study by Sang et al (2014) in U87 cells suggests the importance of HSPB1 phosphorylation in the mechanisms of TMZ resistance; we are beginning to study this important subject.…”

Section: Discussionmentioning

confidence: 95%

Effects of temozolomide (TMZ) on the expression and interaction of heat shock proteins (HSPs) and DNA repair proteins in human malignant glioma cells

Castro

Cayado-Gutiérrez

Zoppino

et al. 2015

Cell Stress and Chaperones

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We previously reported the association of HSPA1A and HSPB1 with high-grade astrocytomas, suggesting that these proteins might be involved in disease outcome and response to treatment. With the aim to better understand the resistance/susceptibility processes associated to temozolomide (TMZ) treatment, the current study was performed in three human malignant glioma cell lines by focusing on several levels: (a) apoptotic index and senescence, (b) DNA damage, and (c) interaction of HSPB1 with players of the DNA damage response. Three human glioma cell lines, Gli36, U87, and DBTRG, were treated with TMZ evaluating cell viability and survival, apoptosis, senescence, and comets (comet assay). The expression of HSPA (HSPA1A and HSPA8), HSPB1, O 6 -methylguanine-DNA methyltransferase (MGMT), MLH1, and MSH2 was determined by immunocytochemistry, immunofluorescence, and Western blot. Immunoprecipitation was used to analyze protein interaction. The cell lines exhibited differences in viability, apoptosis, and senescence after TMZ administration. We then focused on Gli36 cells (relatively unstudied) which showed very low recovery capacity following TMZ treatment, and this was related to high DNA damage levels; however, the cells maintained their viability. In these cells, MGMT, MSH2, HSPA, and HSPB1 levels increased significantly after TMZ administration. In addition, MSH2 and HSPB1 proteins appeared co-localized by confocal microscopy. This colocalization increased after TMZ treatment, and in immunoprecipitation analysis, MSH2 and HSPB1 appeared interacting. In contrast, HSPB1 did not interact with MGMT. We show in glioma cells the biological effects of TMZ and how this drug affects the expression levels of heat shock proteins (HSPs), MGMT, MSH2, and MLH1. In Gli36 cells, the results suggest that interactions between HSPB1 and MSH2, including co-nuclear localization, may be important in determining cell sensitivity to TMZ.

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Section: Discussionmentioning

confidence: 95%

Effects of temozolomide (TMZ) on the expression and interaction of heat shock proteins (HSPs) and DNA repair proteins in human malignant glioma cells

Castro

Cayado-Gutiérrez

Zoppino

et al. 2015

Cell Stress and Chaperones

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“…Sensitization of glioblastoma cell lines to temozolomide [94] In vitro Sorafenib Glioma Heat shock proteins blocking Potentiation of sorafenib pro-apoptotic properties [88] In vitro and in vivo Doxorubicin Breast cancer Quercetin suppressed intratumoral HIF-1α…”

Section: Combination Therapymentioning

confidence: 99%

“…In a similar way, human glioblastoma cells proved to be insensitive to temozolomide alone, since this drug significantly increased HSP27 phosphorylation. However, quercetin or siRNA against HSP27 combined with temozolomide decreased HSP27 phosphorylation and significantly inhibited its expression, leading to glioblastoma cell growth inhibition [94].…”

Section: Combination Therapymentioning

confidence: 99%

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Brito¹,

Ribeiro²,

Abrantes

et al. 2015

CMC

134

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Abstract:Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

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“…TMZ acts by forming O 6 -methylguanine nt, which mispairs with thymine during DNA replication. In consequence, the drug causes cell cycle arrest in G 2 /M phase in astrocytic tumor cells, which finally induces cell death (31). TMZ also reduces the membrane potential of the mitochondrion, releases cytochrome c from this organelle, and increases activated caspases 3 and 9 cell content (32).…”

Section: Discussionmentioning

confidence: 99%

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

Resende

Titze‐de‐Almeida

2018

Oncol Lett

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Abstract. Astrocytic tumors, including astrocytomas and glioblastomas, are the most common type of primary brain tumors. Treatment for glioblastomas includes radiotherapy, chemotherapy with temozolomide (TMZ) and surgical ablation. Despite certain therapeutic advances, the survival time of patients is no longer than 12-14 months. Cancer cells overexpress the neuronal isoform of nitric oxide synthase (nNOS). In the present study, it was examined whether the nNOS enzyme serves a role in the damage of astrocytoma (U251MG and U138MG) and glioblastoma (U87MG) cells caused by TMZ. First, TMZ (250 µM) triggered an increase in oxidative stress at 2, 48 and 72 h in the U87MG, U251MG and U138MG cell lines, as revealed by 2',7'-dichlorofluorescin-diacetate assay. The drug also reduced cell viability, as measured by MTT assay. U87MG cells presented a more linear decline in cell viability at time-points 2, 48 and 72 h, compared with the U251MG and U138MG cell lines. The peak of oxidative stress occurred at 48 h. To examine the role of NOS enzymes in the cell damage caused by TMZ, N(ω)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) were used. L-NAME increased the cell damage caused by TMZ while reducing the oxidative stress at 48 h. The preferential nNOS inhibitor 7-NI also improved the TMZ effects. It caused a 12.8% decrease in the viability of TMZ-injured cells. Indeed, 7-NI was more effective than L-NAME in restraining the increase in oxidative stress triggered by TMZ. Silencing nNOS with a synthetic small interfering (si)RNA (siRNAnNOShum_4400) increased by 20% the effects of 250 µM of TMZ on cell viability (P<0.05). Hoechst 33342 nuclear staining confirmed that nNOS knock-down enhanced TMZ injury. In conclusion, our data reveal that nNOS enzymes serve a role in the damage produced by TMZ on astrocytoma and glioblastoma cells. RNA interference with nNOS merits further studies in animal models to disclose its potential use in brain tumor anticancer therapy.

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Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27

Cited by 82 publications

References 22 publications

Effects of temozolomide (TMZ) on the expression and interaction of heat shock proteins (HSPs) and DNA repair proteins in human malignant glioma cells

Effects of temozolomide (TMZ) on the expression and interaction of heat shock proteins (HSPs) and DNA repair proteins in human malignant glioma cells

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

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