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1.
Int J Mol Sci ; 25(17)2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39273420

RESUMO

Radiation therapy continues to be the cornerstone treatment for malignant brain tumors, the majority of which express wild-type p53. Therefore, the identification of drugs that promote the ionizing radiation (IR)-induced activation of p53 is expected to increase the efficacy of radiation therapy for these tumors. The growth inhibitory effects of CEP-1347, a known inhibitor of MDM4 expression, on malignant brain tumor cell lines expressing wild-type p53 were examined, alone or in combination with IR, by dye exclusion and/or colony formation assays. The effects of CEP-1347 on the p53 pathway, alone or in combination with IR, were examined by RT-PCR and Western blot analyses. The combination of CEP-1347 and IR activated p53 in malignant brain tumor cells and inhibited their growth more effectively than either alone. Mechanistically, CEP-1347 and IR each reduced MDM4 expression, while their combination did not result in further decreases. CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.


Assuntos
Neoplasias Encefálicas , Quinase do Ponto de Checagem 2 , Radiação Ionizante , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Quinase do Ponto de Checagem 2/metabolismo , Quinase do Ponto de Checagem 2/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Fosforilação/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação
2.
Anticancer Res ; 44(9): 3875-3883, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39197897

RESUMO

BACKGROUND/AIM: Glioblastoma is the most aggressive form of brain tumor and has a dismal prognosis; therefore, novel therapeutic approaches based on the mechanisms underlying its aggressive nature are urgently required. A growing body of evidence suggests that neurotransmitters play a key role in modulating the biology of glioblastoma; however, the role of melanocortins remains unclear. MATERIALS AND METHODS: The effects of bremelanotide, a melanocortin receptor agonist, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human glioblastoma cell lines. RESULTS: Bremelanotide reduced survivin expression and induced cell death in glioblastoma cells at concentrations that were not toxic to normal human cells, and both of these effects were canceled in the presence of an antagonist of melanocortin receptors 3 and 4. Bremelanotide-induced cell death was prevented by the forced over-expression of survivin in glioblastoma cells, suggesting that bremelanotide induces glioblastoma cell death by inhibiting the expression of survivin. Bremelanotide also promoted cell death induced by chemotherapeutic agents, such as temozolomide and osimertinib. CONCLUSION: The present results identified melanocortin receptors 3 and 4 as novel and viable therapeutic targets for glioblastoma. Activation of these receptors by bremelanotide may inhibit the expression of survivin, thereby sensitizing glioblastoma cells to cell death.


Assuntos
Glioblastoma , Survivina , alfa-MSH , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Survivina/metabolismo , Survivina/genética , alfa-MSH/farmacologia , alfa-MSH/análogos & derivados , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptores de Melanocortina/agonistas , Receptores de Melanocortina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Morte Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Temozolomida/farmacologia , Antineoplásicos/farmacologia
3.
Int J Mol Sci ; 25(7)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38612758

RESUMO

The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.


Assuntos
Glioblastoma , Glioma , Humanos , Proteína Supressora de Tumor p53/genética , Glioma/tratamento farmacológico , Glioma/genética , Apoptose , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-mdm2/genética
4.
Cancers (Basel) ; 15(17)2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37686602

RESUMO

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2-p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

5.
Int J Mol Sci ; 24(13)2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37445993

RESUMO

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.


Assuntos
Cisplatino , Neoplasias Ovarianas , Humanos , Feminino , Survivina/genética , Survivina/metabolismo , Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Linhagem Celular Tumoral , RNA Mensageiro/genética , Apoptose , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Resistencia a Medicamentos Antineoplásicos , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo
6.
Biomedicines ; 11(7)2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37509605

RESUMO

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.

7.
Anticancer Res ; 43(3): 1131-1138, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36854532

RESUMO

BACKGROUND/AIM: Givinostat is a pan-histone deacetylase (HDAC) inhibitor that has demonstrated excellent tolerability as well as efficacy in patients with polycythemia vera. Accumulating in vitro and in vivo evidence suggests givinostat is also promising as a therapeutic agent targeting glioma stem cells (GSCs), the cancer stem cells of glioblastoma (GBM) considered responsible for its intractable nature. However, it remains to be shown how givinostat impacts the therapeutic effects of temozolomide, a DNA-alkylating agent and the key component of GBM treatment given not only during postoperative radiotherapy but also thereafter as maintenance chemotherapy. MATERIALS AND METHODS: The effects of givinostat and knockdown of O6-methylguanine-DNA methyltransferase (MGMT) or Sp1 on the mRNA and protein expression of relevant genes in human GSC lines were examined by RT-PCR and western blot analyses. The dye exclusion method was used to evaluate cell viability. RESULTS: Givinostat enhanced the cytotoxic activity of temozolomide in GSC lines expressing MGMT, in which the MGMT expression was shown to contribute to their temozolomide resistance. Givinostat inhibited MGMT expression in GSCs and, in parallel, the expression of Sp1, a transcription factor involved in the control of MGMT promoter activity. Knockdown experiments demonstrated Sp1 expression was indeed required for MGMT expression in GSCs. CONCLUSION: Givinostat, in addition to its own cytotoxic activity, sensitizes GSCs to temozolomide by inhibiting Sp1-dependent MGMT expression in GSCs. Combining givinostat with temozolomide could therefore be a rational therapeutic strategy to effectively eliminate GSCs and thus help overcome the therapy resistance of GBM.


Assuntos
Glioblastoma , Glioma , Células-Tronco Neoplásicas , O(6)-Metilguanina-DNA Metiltransferase , Temozolomida , Humanos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/genética , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/metabolismo , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética
8.
Cancers (Basel) ; 16(1)2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-38201546

RESUMO

Uveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investigate in this study the effects on UM cells of CEP-1347, a novel MDM4 inhibitor with a known safety profile in humans. We also examined the impact of CEP-1347 on the protein kinase C (PKC) pathway, known to play a pivotal role in UM cell growth. High-grade UM cell lines were used to analyze the effects of genetic and pharmacological inhibition of MDM4 and PKC, respectively, as well as those of CEP-1347 treatment, on p53 expression and cell viability. The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth. These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM.

9.
Anticancer Res ; 42(10): 4727-4733, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36192008

RESUMO

BACKGROUND/AIM: The development of pharmacological inhibitors targeting negative regulators of p53, such as murine double minute (MDM) 2 and, more recently, MDM4, has been actively pursued as a potential strategy to treat cancers with wild-type p53. We previously showed that CEP-1347, a small molecule kinase inhibitor originally developed for the treatment of Parkinson's disease, suppressed MDM4 expression and activated wild-type p53 in retinoblastoma cells. However, it remains unknown whether CEP-1347 acts as an MDM4 inhibitor and as such activates p53 in other types of human cancer cells. MATERIALS AND METHODS: The effects of CEP-1347 and MDM4 knockdown on the mRNA and protein expression of components of the p53 pathway, including MDM4, in human glioma cell lines with and without p53 mutation were examined by RT-PCR and western blot analyses. Trypan blue dye exclusion was used to examine the effect of CEP-1347 on cell growth. RESULTS: CEP-1347 decreased the expression of MDM4, increase that of p53, and activated the p53 pathway in glioma cells with wild-type p53. Knockdown-mediated inhibition of MDM4 expression in a glioma cell line with wild-type p53 that overexpresses MDM4 resulted in increased p53 expression and activation of the p53 pathway. CEP-1347 preferentially inhibited the growth of glioma cells with wild-type p53 without showing toxicity to normal cells at clinically relevant concentrations. CONCLUSION: Our findings suggest CEP-1347 is a novel inhibitor of MDM4 protein expression and as such activates p53 to inhibit the growth of cancer cells with wild-type p53, including retinoblastoma and glioblastoma.


Assuntos
Glioma , Neoplasias da Retina , Retinoblastoma , Carbazóis , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Humanos , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Mensageiro/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955917

RESUMO

Glioma stem cells (GSCs), the cancer stem cells of glioblastoma multiforme (GBM), contribute to the malignancy of GBM due to their resistance to therapy and tumorigenic potential; therefore, the development of GSC-targeted therapies is urgently needed to improve the poor prognosis of GBM patients. The molecular mechanisms maintaining GSCs need to be elucidated in more detail for the development of GSC-targeted therapy. In comparison with patient-derived GSCs and their differentiated counterparts, we herein demonstrated for the first time that phospholipase C (PLC)ε was highly expressed in GSCs, in contrast to other PLC isoforms. A broad-spectrum PLC inhibitor suppressed the viability of GSCs, but not their stemness. Nevertheless, the knockdown of PLCε suppressed the survival of GSCs and induced cell death. The stem cell capacity of residual viable cells was also suppressed. Moreover, the survival of mice that were transplanted with PLCε knockdown-GSCs was longer than the control group. PLCε maintained the stemness of GSCs via the activation of JNK. The present study demonstrated for the first time that PLCε plays a critical role in maintaining the survival, stemness, and tumor initiation capacity of GSCs. Our study suggested that PLCε is a promising anti-GSC therapeutic target.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Células-Tronco Neoplásicas/metabolismo , Fosfoinositídeo Fosfolipase C , Fosfolipases Tipo C/metabolismo
11.
Medicine (Baltimore) ; 101(31): e29349, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35945740

RESUMO

INTRODUCTION: Postoperative assessment of breast reconstruction results has become increasingly important. In this paper, a unique analysis method with 3-dimensional surface images of patients who were treated with immediate breast reconstruction is presented. PATIENT CONCERNS: Five Japanese women were suspected of having breast cancer and visited our hospital for treatment. DIAGNOSIS: Breast cancer was diagnosed by biopsy, mammography, ultrasonography, computed tomography, and magnetic resonance imaging. INTERVENTIONS: Five patients underwent nipple/skin-sparing mastectomy, concomitant sentinel lymph node biopsy, and immediate breast reconstruction in our hospital. Three cases were reconstructed by extended latissimus dorsi flaps, one was reconstructed by a pedicled transverse rectus abdominis myocutaneous flap, and one was reconstructed by a deep inferior epigastric artery perforator flap. Three-dimensional photographs were taken 1 year postoperatively. The similarity of the breast contours between the reconstructed breast and the nonaffected opposite breast obtained from 3-dimensional images was analyzed. The calculated value is called the breast contour score. OUTCOMES: No recurrence was observed during the follow-up period in any cases. All cases could be analyzed by breast contour score to evaluate the breast shapes. CONCLUSION: The scores become a relative value that ranges from 0 (completely different) to 100 (completely the same). By expressing the score as a relative value, the breast contour score could help us understand the degree of breast symmetry more intuitively.


Assuntos
Neoplasias da Mama , Mamoplastia , Mastectomia Subcutânea , Retalho Miocutâneo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mamoplastia/métodos , Mastectomia , Retalho Miocutâneo/transplante
12.
Int J Mol Sci ; 23(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35897656

RESUMO

Cancer stem cells (CSCs) are in general characterized by higher resistance to cell death and cancer therapies than non-stem differentiated cancer cells. However, we and others have recently revealed using glioma stem cells (GSCs) as a model that, unexpectedly, CSCs have specific vulnerabilities that make them more sensitive to certain drugs compared with their differentiated counterparts. We aimed in this study to discover novel drugs targeting such Achilles' heels of GSCs as anti-GSC drug candidates to be used for the treatment of glioblastoma, the most therapy-resistant form of brain tumors. Here we report that domatinostat (4SC-202), a class I HDAC inhibitor, is one such candidate. At concentrations where it showed no or minimal growth inhibitory effect on differentiated GSCs and normal cells, domatinostat effectively inhibited the growth of GSCs mainly by inducing apoptosis. Furthermore, GSCs that survived domatinostat treatment lost their self-renewal capacity. These results suggested that domatinostat is a unique drug that selectively eliminates GSCs not only physically by inducing cell death but also functionally by inhibiting their self-renewal. Our findings also imply that class I HDACs and/or LSD1, another target of domatinostat, may possibly have a specific role in the maintenance of GSCs and therefore could be an attractive target in the development of anti-GSC therapies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Benzamidas , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioma/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Células-Tronco Neoplásicas/metabolismo
13.
Cancers (Basel) ; 14(7)2022 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-35406478

RESUMO

Despite several clinical trials with encouraging findings, effective standard systemic therapies have yet to be established for malignant meningioma and the prognosis of these patients remains poor. Accumulating preclinical and clinical evidence suggests that gemcitabine is effective against malignant meningioma. To identify drugs with therapeutic effects that may be enhanced in combination with gemcitabine, we screened drugs that have been tested in preclinical and clinical trials for meningioma. In IOMM-Lee and HKBMM malignant meningioma cells, gemcitabine enhanced the growth inhibitory effects of the mTOR inhibitor everolimus, the clinical benefits of which have been demonstrated in patients with meningioma. The synergistic growth inhibitory effects of this combination were accompanied by cellular senescence characterized by an increase in senescence-associated ß-galactosidase activity. To enhance the effects of this combination, we screened senolytic drugs that selectively kill senescent cells, and found that navitoclax, an inhibitor of anti-apoptotic BCL-2 family proteins, effectively reduced the number of viable malignant meningioma cells in combination with everolimus and gemcitabine by inducing apoptotic cell death. The suppression of tumor growth in vivo by the combination of everolimus with gemcitabine was significantly stronger than that by either treatment alone. Moreover, navitoclax, in combination with everolimus and gemcitabine, significantly reduced tumor sizes with an increase in the number of cleaved caspase-3-positive apoptotic cells. The present results suggest that the addition of gemcitabine with or without navitoclax to everolimus is a promising strategy that warrants further evaluation in future clinical trials for malignant meningioma.

14.
Neurooncol Adv ; 3(1): vdab148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765973

RESUMO

BACKGROUND: Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells. METHODS: We examined the radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms. RESULTS: Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells. CONCLUSION: These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.

15.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769063

RESUMO

Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Ácido Fólico/metabolismo , Glioma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioma/metabolismo , Xenoenxertos/efeitos dos fármacos , Xenoenxertos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo
16.
Life (Basel) ; 11(9)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34575034

RESUMO

Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.

17.
Anticancer Res ; 41(9): 4321-4331, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475052

RESUMO

BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. MATERIALS AND METHODS: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. RESULTS: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. CONCLUSION: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Cloridrato de Lurasidona/administração & dosagem , Survivina/metabolismo , Células A549 , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Cloridrato de Lurasidona/farmacologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
PLoS One ; 16(3): e0247587, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33647012

RESUMO

Annual recruitment data of new graduates are manually analyzed by human resources (HR) specialists in industries, which signifies the need to evaluate the recruitment strategy of HR specialists. Different job seekers send applications to companies every year. The relationships between applicants' attributes (e.g., English skill or academic credentials) can be used to analyze the changes in recruitment trends across multiple years. However, most attributes are unnormalized and thus require thorough preprocessing. Such unnormalized data hinder effective comparison of the relationship between applicants in the early stage of data analysis. Thus, a visual exploration system is highly needed to gain insight from the overview of the relationship among applicant qualifications across multiple years. In this study, we propose the Polarizing Attributes for Network Analysis of Correlation on Entities Association (Panacea) visualization system. The proposed system integrates a time-varying graph model and dynamic graph visualization for heterogeneous tabular data. Using this system, HR specialists can interactively inspect the relationships between two attributes of prospective employees across multiple years. Further, we demonstrate the usability of Panacea with representative examples for finding hidden trends in real-world datasets, and we discuss feedback from HR specialists obtained throughout Panacea's development. The proposed Panacea system enables HR specialists to visually explore the annual recruitment of new graduates.


Assuntos
Visualização de Dados , Candidatura a Emprego , Seleção de Pessoal/tendências , Especialização , Recursos Humanos/organização & administração , Educação de Pós-Graduação , Humanos , Japão , Universidades
19.
Neuro Oncol ; 23(6): 945-954, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33556172

RESUMO

BACKGROUND: High-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown. METHODS: We examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity. RESULTS: hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients. CONCLUSIONS: The present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.


Assuntos
Neoplasias Meníngeas , Meningioma , Neoplasias Pancreáticas , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina Quinase/metabolismo , Desoxicitidina Quinase/uso terapêutico , Transportador Equilibrativo 1 de Nucleosídeo , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Gencitabina
20.
Genes (Basel) ; 12(1)2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466690

RESUMO

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an energy source in some CSCs. LDs play central roles not only in lipid storage, but also as a source of endogenous lipid ligands, which are involved in numerous signaling pathways, including the peroxisome proliferator-activated receptor (PPAR) signaling pathway. However, it remains unclear whether LD-derived signal transduction is involved in the maintenance of the properties of CSCs. We investigated the roles of LDs in cancer stemness using pancreatic and colorectal CSCs and isogenic non-CSCs. PPARα was activated in CSCs in which LDs accumulated, but not in non-CSCs, and pharmacological and genetic inhibition of PPARα suppressed cancer stemness. In addition, inhibition of both re-esterification and lipolysis pathways suppressed cancer stemness. Our study suggested that LD metabolic turnover accompanying PPARα activation is a promising anti-CSC therapeutic target.


Assuntos
Neoplasias Colorretais/metabolismo , Gotículas Lipídicas/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , PPAR alfa/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metabolismo Energético , Células HT29 , Humanos , Gotículas Lipídicas/patologia , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , PPAR alfa/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Transdução de Sinais
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