Antitumor activity of gemcitabine against high-grade meningioma<i>in vitro</i>and<i>in vivo</i>

Takeda, Hiroyuki; Okada, Masashi; Kuramoto, Kenta; Sakaki, Hirotsugu; Sanomachi, Tomomi; Seino, Shizuka; Yoshioka, Takashi; Hirano, Hirofumi; Arita, Kazunori; Kitanaka, Chifumi

doi:10.18632/oncotarget.18827

Cited by 19 publications

(18 citation statements)

References 53 publications

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“…Viable and dead cells were identified by their ability and inability to exclude vital dyes, respectively . Briefly, cells were treated with drugs as described and stained with 0.2% trypan blue for 1 min at room temperature (RT), and the number of viable and dead cells was determined using a haemocytometer.…”

Section: Methodsmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

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Section: Methodsmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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“…Dead cells (%) were defined as 100 × ‘the number of dead cells’/(‘the number of viable cells’ + ‘the number of dead cells’). The following formula was used to obtain IC 50 values, as previously reported [65]: IC 50 = 10 [log(A/B) × (50-C)]/[(D-C) + Log(B)] , where A and B are the corresponding concentrations of the test drug directly above and below 50% inhibition, respectively, and C and D are the percentages of inhibition directly below and above 50% inhibition, respectively.…”

Section: Methodsmentioning

confidence: 99%

Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Sanomachi

Togashi

Sugai

et al. 2019

Cancers

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Spironolactone, a classical diuretic drug, is used to treat tumor-associated complications in cancer patients. Spironolactone was recently reported to exert anti-cancer effects by suppressing DNA damage repair. However, it currently remains unclear whether spironolactone exerts combinational effects with non-DNA-damaging anti-cancer drugs, such as gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Using the cancer cells of lung cancer, pancreatic cancer, and glioblastoma, the combinational effects of spironolactone with gemcitabine and osimertinib, a third-generation EGFR-TKI, were examined in vitro with cell viability assays. To elucidate the underlying mechanisms, we investigated alterations induced in survivin, an anti-apoptotic protein, by spironolactone as well as the chemosensitization effects of the suppression of survivin by YM155, an inhibitor of survivin, and siRNA. We also examined the combinational effects in a mouse xenograft model. The results obtained revealed that spironolactone augmented cell death and the suppression of cell growth by gemcitabine and osimertinib. Spironolactone also reduced the expression of survivin in these cells, and the pharmacological and genetic suppression of survivin sensitized cells to gemcitabine and osimertinib. This combination also significantly suppressed tumor growth without apparent adverse effects in vivo. In conclusion, spironolactone is a safe candidate drug that exerts anti-cancer effects in combination with non-DNA-damaging drugs, such as gemcitabine and osimertinib, most likely through the suppression of survivin.

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“…A screen of 11 chemotherapeutic agents commonly used against a variety of cancers, including mainstays such as temozolomide, platinum-based drugs, and methotrexate, has identified gemcitabine as being particularly effective against grade II M-16-N and grade III HKBMM meningioma cells in vitro and in vivo. 116 A grade III anaplastic meningioma PDX model has also been shown to be sensitive to an oncolytic herpesvirus. 117 Protein phosphatase 2A (PP2A) inhibitor LB-100 doubled the survival benefit of radiotherapy in mice with intracranial xenografts of human IOMM-Lee immortalized meningioma cells.…”

Section: Neuro-oncologymentioning

confidence: 99%

Molecular and translational advances in meningiomas

et al. 2019

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Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

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Antitumor activity of gemcitabine against high-grade meningiomain vitroandin vivo

Cited by 19 publications

References 53 publications

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Molecular and translational advances in meningiomas

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