Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma

2020 ◽  
Vol 26 (36) ◽  
pp. 4675-4684 ◽  
Author(s):  
Shabierjiang Jiapaer ◽  
Takuya Furuta ◽  
Yu Dong ◽  
Tomohiro Kitabayashi ◽  
Hemragul Sabit ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Drug Screening ◽  
Therapeutic Agent ◽  
Gelatin Zymography ◽  
Therapeutic Agents ◽  
Drug Candidate ◽  
Potential Therapeutic Agent ◽  
Sphere Formation ◽  
Improve Patient

Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

scholarly journals DDIS-05. IDENTIFICATION OF 2-FLUORO PALMITIC ACID AS A POTENTIAL THERAPEUTIC AGENT AGAINST GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi66-vi66
Author(s):  
Shabierjiang Jiapaer ◽  
Yu Dong ◽  
Tomohiro Kitabayashi ◽  
Taskuya Furuta ◽  
Hemragul Sabit ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cell Lines ◽  
Glioma Cell ◽  
Therapeutic Agent ◽  
Drug Repositioning ◽  
Dependent Manner ◽  
Potential Therapeutic Agent ◽  
Glioma Cell Lines ◽  
Sphere Formation ◽  
Novel Therapeutic

Abstract BACKGROUND Glioblastoma (GBM) represents the most aggressive and frequent type of primary malignant brain tumors with a dismal clinical outcome. Though adjuvant temozolomide (TMZ) chemotherapy followed by surgical resection can extend patient`s post-operative survival, a considerable number of GBM cases are refractory to TMZ. Novel therapeutic agents that can overcome chemoresistance against TMZ are urgent. Drug repositioning is a process of identifying new indications for existing drugs and provides potential possibilities to discover new drugs. In this study, we explored novel anti-glioma agents which enhances the effect of TMZ with the strategy of drug repositioning. METHODS Drug library which contains 1300 diverse chemical compounds was screened using 2 kinds of glioma stem cell (GSC) lines to select novel therapeutic candidate. The effect of candidate drug on the proliferation of GSCs was estimated by sphere formation assay. To evaluate its efficacy against glioma cell biology, proliferation assay, matrigel invasion assay were performed. To clarify the mechanism of drug effects, we investigated target molecules by gelatin zymography and western blot. RESULTS Acyl CoA synthetase inhibitor named 2-fluoropalmitic acid (2-FPA) was selected as a novel candidate. 2-FPA suppressed proliferation of glioma cell lines by single administration and/or combination with TMZ. The sphere formation of GSCs was suppressed by combination therapy. Combination therapy enhanced TMZ effect. 2-FPA also suppressed invasion of glioma cell lines in a dose dependent manner. 2-FPA suppressed MMP-2 activity and phosphorylation of STAT3. CONCLUSION 2-FPA was identified as a novel potential therapeutic agent against GBM.

scholarly journals The Evolving Reduction of Vancomycin and Daptomycin Susceptibility in MRSA—Salvaging the Gold Standards with Combination Therapy

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 762
Author(s):  
Taylor Morrisette ◽  
Sara Alosaimy ◽  
Jacinda C. Abdul-Mutakabbir ◽  
Razieh Kebriaei ◽  
Michael J. Rybak
Keyword(s):  
Combination Therapy ◽  
Patient Outcomes ◽  
Treatment Option ◽  
Standard Treatment ◽  
Primary Treatment ◽  
Alternative Approach ◽  
Improve Patient ◽  
Substantial Morbidity

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with substantial morbidity and mortality. Vancomycin (VAN) has been used as the gold standard treatment for invasive MRSA infections for decades but, unfortunately, the reliance of VAN as the primary treatment option against these infections has led to a reduction in VAN susceptibility in MRSA isolates. Although daptomycin (DAP) is another common treatment option against invasive MRSA infections, it has been shown that the development of VAN resistance can lead to DAP nonsusceptibility. VAN or DAP backbone regimens in combination with other antibiotics has been advocated as an alternative approach to improve patient outcomes in VAN/DAP-susceptible infections, enhance outcomes in infections caused by isolates with reduced VAN/DAP susceptibility, and/or prevent the emergence of VAN/DAP resistance or further resistance. A peer-reviewed literature search was conducted using Medline, Google Scholar and PubMed databases. The primary purpose of this review is to describe the mechanisms and epidemiology of MRSA isolates with a reduction in VAN and/or DAP susceptibility, evaluate in vitro and in vivo literature describing combination therapy (CT) against MRSA isolates with reduced VAN and/or DAP susceptibility and describe studies involving the clinical outcomes of patients treated with CT against invasive MRSA infections.

scholarly journals Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.

1997 ◽  
Vol 41 (11) ◽  
pp. 2333-2338 ◽  
Author(s):  
G K Abruzzo ◽  
A M Flattery ◽  
C J Gill ◽  
L Kong ◽  
J G Smith ◽  
...  
Keyword(s):  
Mouse Models ◽  
Therapeutic Agent ◽  
Drug Candidate ◽  
Disseminated Candidiasis ◽  
Intraperitoneal Dose ◽  
Effective Doses ◽  
Candida Lusitaniae ◽  
Disseminated Aspergillosis ◽  
Body Weight Dose

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.

Time-lag combination therapy for cerebral ischemia using the FNK protein transduction technology and an immunosuppressant, I: In vivo study

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S57-S57
Author(s):  
Ken-ichiro Kasura ◽  
Megumi Watanabe ◽  
Kumiko Takahashi ◽  
Genki Mizukoshi ◽  
Seiji Ohkubo ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Combination Therapy ◽  
Time Lag ◽  
In Vivo Study ◽  
Protein Transduction

In Vivo Wound Healing Activity of Spirulina platensis

2019 ◽  
Vol 18 (1) ◽  
pp. 06-16
Author(s):  
R. Seghiri ◽  
A. Essamri
Keyword(s):  
Wound Healing ◽  
Spirulina Platensis ◽  
Therapeutic Agent ◽  
Conventional Medicine ◽  
Folk Medicine ◽  
Chemical Burns ◽  
Amount Of Substance ◽  
Test Population ◽  
Wound Healing Activity

Spirulina is a microalga used in traditional folk medicine in Morocco for the treatment of various health disorders. The wound healing activity of Moroccan Spirulina is unknown. In the current study, aqueous extracts of Spirulina platensis were investigated for acute toxicity and wound healing activity in Swiss Albino mice and White New Zealand rabbits, respectively. The LD50 (amount of substance required to kill 50% of the test population) of the microalga was greater than 5,000 mg/kg. Healing after application of the same amount of ointment on differently induced (mechanical, chemical, and thermal) wounds was about the same, over five weeks. Aqueous extract had remarkable healing activity on rabbits’ skin, possessing significantly greater healing effect for mechanical and chemical burns than controls. Moreover, the hair growing time was faster in treated groups; Spirulina-treated groups did not show any contamination with microbes compared to others. This study affirms that Spirulina platensis can be considered as a potential therapeutic agent for wound healing not only as a complementary medicine but also in conventional medicine.

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