Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Yamamoto, Masahiro; Togashi, Keita; Sugai, Asuka; Okada, Masashi; Kitanaka, Chifumi

doi:10.3390/cancers14071706

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…The dose-timing regimen of ABT263 (50 mg/kg/day, oral gavage; A3007, Apexbio) is described in detail in the text. The dosage and mode of administration of ABT263 were determined according to previous studies [ 27 , 32 ].…”

Section: Methodsmentioning

confidence: 99%

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Xie¹,

Tang²,

Chen³

et al. 2023

Aging and disease

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Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRβ/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRβ/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.

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Section: Methodsmentioning

confidence: 99%

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Xie¹,

Tang²,

Chen³

et al. 2023

Aging and disease

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“…Subsequent phase I and II studies also found that everolimus was well tolerated and delayed disease progression in patients with advanced HCC [255]. Yamamoto et al screened anti-aging drugs that selectively kill SnCs and found that the combination of anti-apoptotic Bcl-2 family protein inhibitor navitoclax with evolimus and gemcitabine could increase the number of cleaved caspase-3-positive apoptotic cells, effectively reducing the number of surviving cells in malignant meningioma and tumor size [256]. It was also found that everolimus, in combination with gemcitabine, inhibited tumor growth in vivo significantly more than either treatment alone [256].…”

Section: Rapamycin and Its Derivativesmentioning

confidence: 99%

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

2024

Aging dis

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Cellular senescence is characterized by the permanent arrest of cell proliferation and is a response to endogenous and exogenous stress. The continuous accumulation of senescent cells (SnCs) in the body leads to the development of aging and age-related diseases (such as neurodegenerative diseases, cancer, metabolic diseases, cardiovascular diseases, and osteoarthritis). In the face of the growing challenge of aging and age-related diseases, several compounds have received widespread attention for their potential to target SnCs. As a result, senolytics (compounds that selectively eliminate SnCs) and senomorphics (compounds that alter intercellular communication and modulate the behavior of SnCs) have become hot research topics in the field of anti-aging. In addition, strategies such as combination therapies and immune-based approaches have also made significant progress in the field of antiaging therapy. In this article, we discuss the latest research on anti-aging targeting SnCs and gain a deeper understanding of the mechanism of action and impact of different anti-aging strategies on aging and age-related diseases, with the aim of providing more effective references and therapeutic ideas for clinical anti-aging treatment in the face of the ever-grave challenges of aging and age-related diseases.

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“…Mouse xenograft studies were conducted as previously described [24,25]. After assessing cell viability using the dye exclusion method, 1×10 6 viable IOMM-Lee cells suspended in 200 µL PBS were subcutaneously implanted bilaterally into the flanks of 5-to 7-week-old male BALB/cAJcl-nu/nu mice (CLEA Japan, Tokyo, Japan) anesthetized by an intraperitoneal injection of butorphanol, midazolam, and medetomidine (5, 4, and 0.3 mg per kg body weight, respectively).…”

Section: Mouse Studymentioning

confidence: 99%

The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo

et al. 2023

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A significant proportion of meningiomas are clinically aggressive, but there is currently no effective chemotherapy for meningiomas. An increasing number of studies have been conducted to develop targeted therapies, yet none have focused on the p53 pathway as a potential target. In this study, we aimed to determine the in vitro and in vivo effects of CEP-1347, a small-molecule inhibitor of MDM4 with known safety in humans. The effects of CEP-1347 and MDM4 knockdown on the p53 pathway in human meningioma cell lines with and without p53 mutation were examined by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 were examined in vitro and in a mouse xenograft model of meningioma. In vitro, CEP-1347 at clinically relevant concentrations inhibited MDM4 expression, activated the p53 pathway in malignant meningioma cells with wild-type p53, and exhibited preferential growth inhibitory effects on cells expressing wild-type p53, which was mostly mimicked by MDM4 knockdown. CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose that was far lower than the maximum dose that could be safely given to humans. Our findings suggest targeting the p53 pathway with CEP-1347 represents a novel and viable approach to treating aggressive meningiomas.

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Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

Cited by 6 publications

References 51 publications

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo

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