Increased glucose metabolism is now recognized as an emerging hallmark of cancer. Recent studies have shown that glucose metabolism is even more active in cancer stem cells (CSCs), a rare population ...of cancer cells with the capacity to self-renew and initiate tumors, and that CSCs are dependent on glycolysis for their survival/growth. However, the role of glucose metabolism in the control of their self-renewal and tumor-initiating capacity per se still remains obscure. Moreover, much remains unknown as to which of the numerous molecules involved in the glucose metabolism is suitable as a target to control CSCs. Here we demonstrate that the facilitative glucose transporter GLUT1 is essential for the maintenance of pancreatic, ovarian, and glioblastoma CSCs. Notably, we found that WZB117, a specific GLUT1 inhibitor, could inhibit the self-renewal and tumor-initiating capacity of the CSCs without compromising their proliferative potential in vitro. In vivo, systemic WZB117 administration inhibited tumor initiation after implantation of CSCs without causing significant adverse events in host animals. Our findings indicate GLUT1-dependent glucose metabolism has a pivotal role not only in the growth and survival of CSCs but also in the maintenance of their stemness and suggest GLUT1 as a promising target for CSC-directed cancer therapy.
Chemical reactions at the interface of reactive solutions are of importance for a full understanding of solution reactions. We investigate the chemical reaction induced by the collision of two ...droplets. The extent of the reaction is measured by analyzing spectra and images of the Raman scattered light emerging from the interface of the colliding droplets of H2SO4 and NH3 aqueous solutions. The obtained product concentration is lower than that expected from a simple diffusion model. The result indicates that a fresh interface is produced at the periphery of the mixing region of the colliding droplets. This study provides the basis to extend this method to measure rapid chemical reactions at the interface of colliding droplets.
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®), 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 IC50 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.
The OXPHOS activity and expression of mtDNA‐related proteins were higher in glioma stem cells (GSCs) than in differentiated GSCs. Moreover, GSC survival was dependent on OXPHOS activity. We identified verteporfin (VPF; a drug that is used clinically for macular degeneration) as a GSC‐OXPHOS‐targeting drug. VPF induced the death of GSCs selectively possibly due to mitochondrial dysfunction. Thus, VPF may be a potential therapeutic option for glioblastoma by targeting mitochondrial OXPHOS.
A novel coupling device composed of a combination of microlens and pillar having an approximately 8lm diameter and 20lm height and grown from single-mode fiber (SMF) core end is proposed. This device ...was successfully fabricated by using a self-written waveguide and dipping method with UV-curable resin. Theoretical and experimental studies were done. A high coupling efficiency of more than -0.97dB was obtained for coupling to an ultrahigh numerical aperture (0.41) SMF with a spot diameter of 3.7μm at a 1.55μm wavelength in place of a silicon chip with an integrated spot-size converter. In contrast, it is only -4.0dB by a conventional SMF.
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.
The annealing of an AlN buffer layer in a carbon-saturated N2-CO gas on a sapphire substrate was investigated. The crystal quality of the buffer layer was significantly improved by annealing at ...1650-1700 °C. An AlN buffer layer with a thickness of 300 nm was grown by metalorganic vapor phase epitaxy (MOVPE), and was annealed at 1700 °C for 1 h. We fabricated a 2-µm-thick AlN layer on the annealed AlN buffer layer by MOVPE. The full widths at half maximum of the (0002)- and ()-plane X-ray rocking curves were 16 and 154 arcsec, respectively, and the threading dislocation density was 4.7 × 108 cm−2.
Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) ...endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.
Nuclear protein of the testis (NUT) midline carcinoma (NMC) is a rare malignant tumor expressing NUT with BRD4/3 rearrangements and is sometimes misdiagnosed as germinoma, especially in ...alpha-fetoprotein (AFP)-elevated cases. A 28-year-old man had a mediastinal tumor with multiple bone metastases and elevated AFP levels. Imaging/laboratory findings led to a pathological diagnosis of extragonadal germinoma. After unsuccessful treatment with etoposide-cisplatin, he was re-diagnosed with sarcoma due to vimentin-positive findings. He was treated with adriamycin-ifosfamide, which resulted in disease-control. A posthumous examination clarified the NUT rearrangement. Even in cases with characteristic findings, such as elevated AFP levels and vimentin positivity, NMC should be considered as a differential diagnosis. We note, however, that adriamycin-ifosfamide has some efficacy in such cases.
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.
Use of epidermal growth factor receptor (EGFR) inhibitors represented by gefitinib and erlotinib has become the standard of treatment for non-small-cell lung cancers (NSCLCs) with activating EGFR ...mutations. However, the majority of NSCLCs, which overexpress EGFR without such mutations, are resistant to EGFR inhibitors, and the mechanism(s) behind such primary resistance of NSCLCs without activating EGFR mutations to EGFR inhibitors still remains poorly understood. Here in this study, we show that glucose metabolism mediated by GLUT1, a facilitative glucose transporter, is involved in gefitinib resistance of NSCLC cells. We found that GLUT1 expression and glucose uptake were increased in resistant NSCLC cells after gefitinib treatment and that genetic as well as pharmacological inhibition of GLUT1 sensitized not only NSCLC cells with primary resistance but also those with acquired resistance to gefitinib.
, the combination of systemic gefitinib and a GLUT1 inhibitor, both of which failed to inhibit tumor growth when administered alone, significantly inhibited the growth of xenograft tumors formed by the implantation of NSCLC cells with wild-type EGFR (wt-EGFR). Since our data indicated that GLUT1 was similarly involved in erlotinib resistance, our findings suggest that the activity of GLUT1-mediated glucose metabolism could be a critical determinant for the sensitivity of NSCLC cells to EGFR inhibitors and that concurrent GLUT1 inhibition may therefore be a mechanism-based approach to treating NSCLCs resistant to EGFR inhibitors, including those with wt-EGFR.
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