Mitigating temozolomide resistance in glioblastoma via DNA damage-repair inhibition

Sorribes, Inmaculada C.; Handelman, Samuel K.; Jain, Harsh

doi:10.1098/rsif.2019.0722

Cited by 17 publications

(10 citation statements)

References 60 publications

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“…Although the use of TMZ improves the general survival rate of patients [ 12 ], the overall therapeutic effect and prognosis are unsatisfactory. The main factor limiting clinical efficiency is the development of resistance to TMZ in the majority of GBM patients [ 13 , 14 ], Overcoming this problem has become a key target for GBM research.…”

Section: Introductionmentioning

confidence: 99%

SOCS5 contributes to temozolomide resistance in glioblastoma by regulating Bcl-2-mediated autophagy

Han

Yang

et al. 2022

Bioengineered

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Temozolomide (TMZ) is the primary chemotherapeutic drug for treating glioblastoma (GBM); however, the final clinical outcome is considerably limited by the poor response and resistance to TMZ. Although autophagy is thought to be associated with chemotherapy resistance and cancer cell survival, the precise molecular mechanisms underlying this process remain elusive. The suppressor of cytokine signaling (SOCS) family is widely distributed in vivo and exerts a range of effects on tumors; however, the expression pattern and role of SOCS in GBM remains unknown. In this study, we determined that high SOCS5 expression level was associated with poor prognosis and TMZ resistance in GBM. TMZ induced an increase in SOCS5 expression level and upregulated autophagy during the acquisition of drug resistance. The observed increase in the extent of autophagy was mediated by SOCS5. Mechanistically, SOCS5 enhances the transcription of Bcl-2. Knockdown of SOCS5 inhibited TMZ chemoresistance in GBM cells through the inhibition of Bcl-2 recruited autophagy; upregulation of Bcl-2 blocked this effect. In summary, our findings revealed the involvement and underlying mechanism of SOCS5 in TMZ resistance. SOCS5 plays a critical role in GBM chemoresistance and may serve as a novel prognostic marker and therapeutic target for chemotherapeutically treating drug-resistant GBM.

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Section: Introductionmentioning

confidence: 99%

SOCS5 contributes to temozolomide resistance in glioblastoma by regulating Bcl-2-mediated autophagy

Han

Yang

et al. 2022

Bioengineered

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“…The 5-year survival rate is still very low. Current therapeutic strategies for GBM, such as surgery followed by radiation or chemotherapy, usually turn out to be invalid owing to low response or resistance 6 . In a short period of time, GBM cells are able to migrate and invade the surrounding normal brain tissue.…”

Section: Discussionmentioning

confidence: 99%

Case report of pulmonary metastasis in a male Wistar rat glioblastoma model

Zhou

Shi

et al. 2021

J Toxicol Pathol

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Glioblastoma (GBM) is a highly aggressive central nervous system cancer. Its extracranial metastases have rarely been reported in the past few decades. Moreover, the pathogenesis of extracranial GBM metastases remains unclear. Here, we report a case of pulmonary metastasis in a male Wistar rat of C6 GBM model. This reported Wistar male rat was one of the experimental control group without any other intervention except for C6 GBM cells orthotopic implantation. On postoperative day 15, the animal which was reported in this study showed highly cellular, pleomorphic, tumor with nuclear atypia in the brain (Ki67, approximately 65.7%) and lungs (Ki67, 49.5%). Tumor cells in the lung showed immunoreactivity for glial fibrillary acidic protein. Inflammatory CD68 + cell infiltration, weakly positive E-cadherin, and strongly positive staining for vimentin were observed both in tumors in the brain and lungs. Based on further morphological analysis, we speculate that the potential metastatic route into the lung might be hematogenous metastasis.

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“…The main mechanism of TMZ for treating glioma is to first deliver its methyl group to tumor cell DNA, causing DNA methylation and DNA damage in tumor cells. This in turn inhibits tumor cell proliferation, while inducing cell apoptosis ( 62 , 69 ). TMZ destroys the DNA of tumor cells by delivering the active methyl groups to O 6 and N 7 position of guanine and the N 3 position of adenine to form cytotoxic O 6 -methylguanine ( O 6 -MeG), N 7 -methylguanine ( N 7 -MeG) and N 3 -methyladenine ( N 3 -MeA) ( 70 ).…”

Section: Temozolomidementioning

confidence: 99%

Research progress of anti-glioma chemotherapeutic drugs (Review)

et al. 2022

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Glioma is the most common primary intracranial malignancy in the central nervous system. At present, the most important treatment option is surgical resection of the tumor combined with radiotherapy and chemotherapy. The principle of operation is to remove the tumor to the maximal extent on the basis of preserving brain function. However, prominent invasive and infiltrative proliferation of glioma tumor cells into the surrounding normal tissues frequently reduces the efficacy of treatment. This in turn worsens the prognosis, because the tumor cannot be completely removed, which can readily relapse. Chemotherapeutic agents when applied individually have demonstrated limited efficacy for the treatment of glioma. However, multiple different chemotherapeutic agents can be used in combination with other treatment modalities to improve the efficacy while circumventing systemic toxicity and drug resistance. Therefore, it is pivotal to unravel the inhibitory mechanism mediated by the different chemotherapeutic drugs on glioma cells in preclinical studies. The aim of the present review is to provide a summary for understanding the effects of different chemotherapeutic drugs in glioma, in addition to providing a reference for the preclinical research into novel chemotherapeutic agents for future clinical application.

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Mitigating temozolomide resistance in glioblastoma via DNA damage-repair inhibition

Cited by 17 publications

References 60 publications

SOCS5 contributes to temozolomide resistance in glioblastoma by regulating Bcl-2-mediated autophagy

SOCS5 contributes to temozolomide resistance in glioblastoma by regulating Bcl-2-mediated autophagy

Case report of pulmonary metastasis in a male Wistar rat glioblastoma model

Research progress of anti-glioma chemotherapeutic drugs (Review)

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