Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance

Huang, Haohao; Zhang, Songyang; Li, Yuanyuan; Liu, Zhaodan; Mi, Lanjuan; Cai, Yan; Wang, Xinzheng; Chen, Li-Shu; Ran, Haowen; Xiao, Dake; Li, Fangye; Wu, Jiaqi; Li, Tingting; Han, Qin; Chen, Liang; Pan, Xin; Li, Yong; Li, Tao; He, Kun; Li, Ailing; Zhang, Xuemin; Zhou, Tao; Xia, Qing; Man, Jianghong

doi:10.1038/s41467-021-24108-6

Cited by 90 publications

(49 citation statements)

References 57 publications

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“…Assessment should also recognise the contribution of cancer stem cells (CSCs), which are involved in both tumour initiation and growth, as well as modulating resistance to chemotherapy and radiotherapy 5 limiting long-term survival. Spheroid formation has been proposed as a robust, independent predictor of glioma tumour progression 6 and the presence of glioma stem cells (GSCs), which are enriched in spheroids, may be connected to the drug resistance of GBM due to their enhanced antioxidant defence 7 and elevated DNA repair capacity. 8 In this report we firstly compared the growth inhibitory capacity of SFN from SFX-01 versus reference SFN using a series of tumour cell lines.…”

Section: Introductionmentioning

confidence: 99%

Effect of SFX-01 on proliferation of human glioblastoma cell lines

Leung

Wright

Baguley

2021

Preprint

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Glioblastoma (GBM) is the most aggressive and lethal of brain tumours and there is a clear need for novel therapies. SFX-01, a stabilised formulation of sulforaphane (SFN) that is complexed with alpha-cyclodextrin, is being investigated as a potential anticancer drug. As part of this investigation, we have determined its effect on the proliferation of a series of tumour cell lines. Growth-inhibitory concentrations (IC50 values) of SFX-01 and SFN were highly correlated but showed a divergence at higher drug concentrations that is likely to reflect drug binding to alpha-cyclodextrin complexes. Because SFN is redox-sensitive, we also compared the effects of these drugs on four GBM lines that had been derived and cultured under physiological oxygen (5%) conditions. Comparisons were also made using a three-dimensional spheroid model, used to mimic the in vivo state of glioblastomas and to simulate barriers to drug delivery in vivo. SFN and SFX-01 inhibited proliferation of four GBM cell lines in monolayers as well as in spheroids, while alpha-cyclodextrin had no significant effect. Our results are consistent with the hypothesis that SFN is complexed and protected by the cyclodextrin cage but that the free drug concentration is sufficient to inhibit cell growth. We envision that SFX-01 will have improved pharmacokinetic properties in vivo, warranting further pre-clinical investigation and clinical development.

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Section: Introductionmentioning

confidence: 99%

Effect of SFX-01 on proliferation of human glioblastoma cell lines

Leung

Wright

Baguley

2021

Preprint

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“…Prohibitin regulates mitochondrial ROS production in GICs, thus facilitating their RT resistance [34]. Prohibitin may be found upregulated in GICs and is associated with malignant gliomas progression.…”

Section: Advances In Rtmentioning

confidence: 99%

“…Knockout of prohibitin dramatically elevates ROS levels, thereby inhibiting GIC self-renewal. The deletion or pharmacological inhibition of prohibitin slows tumor growth and sensitizes tumors to RT, thus providing significant survival benefits in GIC-derived orthotopic tumors and GB patient-derived xenografts models [34].…”

Section: Advances In Rtmentioning

confidence: 99%

Radiotherapy of High-Grade Gliomas: First Half of 2021 Update with Special Reference to Radiosensitization Studies

Fròsina

2021

IJMS

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Albeit the effort to develop targeted therapies for patients with high-grade gliomas (WHO grades III and IV) is evidenced by hundreds of current clinical trials, radiation remains one of the few effective therapeutic options for them. This review article analyzes the updates on the topic “radiotherapy of high-grade gliomas” during the period 1 January 2021–30 June 2021. The high number of articles retrieved in PubMed using the search terms (“gliom* and radio*”) and manually selected for relevance indicates the feverish research currently ongoing on the subject. During the last semester, significant advances were provided in both the preclinical and clinical settings concerning the diagnosis and prognosis of high-grade gliomas, their radioresistance, and the inevitable side effects of their treatment with radiation. The novel information concerning tumor radiosensitization was of special interest in terms of therapeutic perspective and was discussed in detail.

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“…Excess ROS produced by chemotherapy may induce irreversible cell damage and cause tumor cell death [28,29]. However, some cancer cells may stay in quiescence by overexpressing antioxidant enzymes to maintain low levels of ROS, even lower than that of normal cells, to evade chemotherapy-induced cell death [30,31]. Such quiescent cancer cells are highly relevant to tumor recurrence and have several characteristics similar to dormant cancer cells, indicating potential relationships between redox and cancer dormancy [32].…”

Section: Introductionmentioning

confidence: 99%

Redox Control of the Dormant Cancer Cell Life Cycle

Huang

Hui

et al. 2021

Cells

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Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells.

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Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance

Cited by 90 publications

References 57 publications

Effect of SFX-01 on proliferation of human glioblastoma cell lines

Effect of SFX-01 on proliferation of human glioblastoma cell lines

Radiotherapy of High-Grade Gliomas: First Half of 2021 Update with Special Reference to Radiosensitization Studies

Redox Control of the Dormant Cancer Cell Life Cycle

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