• Title/Summary/Keyword: Drug combination

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Modulation of Autophagy is a Potential Strategy for Enhancing the Anti-Tumor Effect of Mebendazole in Glioblastoma Cells

  • Jo, Seong Bin;Sung, So Jung;Choi, Hong Seok;Park, Jae-Sung;Hong, Yong-Kil;Joe, Young Ae
    • Biomolecules & Therapeutics
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    • v.30 no.6
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    • pp.616-624
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    • 2022
  • Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has been suggested as a repositioning candidate for the treatment of brain tumors. However, the efficacy of MBZ needs further study to improve the beneficial effect on the survival of those patients. In this study, we explored a novel strategy to improve MBZ efficacy using a drug combination. When glioblastoma cells were treated with MBZ, cell proliferation was dose-dependently inhibited with an IC50 of less than 1 µM. MBZ treatment also inhibited glioblastoma cell migration with an IC50 of less than 3 µM in the Boyden chamber migration assay. MBZ induced G2-M cell cycle arrest in U87 and U373 cells within 24 h. Then, at 72 h of treatment, it mainly caused cell death in U87 cells with an increased sub-G1 fraction, whereas polyploidy was seen in U373 cells. However, MBZ treatment did not affect ERK1/2 activation stimulated by growth factors. The marked induction of autophagy by MBZ was observed, without any increased expression of autophagy-related genes ATG5/7 and Beclin 1. Co-treatment with MBZ and the autophagy inhibitor chloroquine (CQ) markedly enhanced the anti-proliferative effects of MBZ in the cells. Triple combination treatment with temozolomide (TMZ) (another autophagy inducer) further enhanced the anti-proliferative effect of MBZ and CQ. The combination of MBZ and CQ also showed an enhanced effect in TMZ-resistant glioblastoma cells. Therefore, we suggest that the modulation of protective autophagy could be an efficient strategy for enhancing the anti-tumor efficacy of MBZ in glioblastoma cells.

Epidemiology of PAH in Korea: An Analysis of the National Health Insurance Data, 2002-2018

  • Albert Youngwoo Jang;Hyeok-Hee Lee;Hokyou Lee;Hyeon Chang Kim;Wook-Jin Chung
    • Korean Circulation Journal
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    • v.53 no.5
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    • pp.313-327
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    • 2023
  • Background and Objectives: Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Recent advances in PAH-specific drugs have improved its outcomes, although the healthcare burden of novel therapeutics may lead to a discrepancy in outcomes between developing and developed countries. We analyzed how the epidemiology and clinical features of PAH has changed through the rapidly advancing healthcare infrastructure in South Korea. Methods: PAH was defined according to a newly devised 3-component algorithm. Using a nationwide health insurance claims database, we delineated annual trends in the prevalence, incidence, medication prescription pattern, and 5-year survival of PAH in Korea. Cumulative survival and potential predictors of mortality were also assessed among 2,151 incident PAH cases. Results: Between 2002 or 2004 and 2018, the prevalence and incidence of PAH increased 75-fold (0.4 to 29.9 per million people) and 12-fold (0.5 to 6.3 per million person-years), respectively. The proportion of patients on combination PAH-specific drug therapy has also steadily increased up to 29.0% in 2018. Among 2,151 incident PAH cases (median [interquartile range] age, 50 [37-62] years; 67.2% female), the 5-year survival rate and median survival duration were 71.8% and 13.1 years, respectively. Independent predictors of mortality were age, sex, etiology of PAH, diabetes, dyslipidemia, and chronic kidney disease. Conclusions: This nationwide study delineated that the prevalence and incidence of PAH have grown rapidly in Korea since the early 2000s. The use of combination therapy has also increased, and the 5-year survival rate of PAH in Korea was similar to those in western countries.

Anti-Varicella Zoster Virus Activity of Water Soluble Substance from Elfvingia applanata Alone and in Combinations with Acyclovir and Vidarabine

  • Kim, Soo-Dong;Eo, Seong-Kug;Kim, Young-So;Han, Seong-Sun
    • Natural Product Sciences
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    • v.5 no.2
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    • pp.107-111
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    • 1999
  • To investigate less toxic antiviral agents from Basidiomycetes, EA, the water soluble substance, was isolated from the carpophores of Elfvingia applanata (pers.) Karst. Anti-varicella zoster virus (Oka strain; anti-VZV/Oka) activity of EA was examined in MRC-5 cells by plaque reduction assay in vitro. And the combined antiviral effects of EA with nucleoside anti-VZV agents, acyclovir and vidarabine, were examined on the multiplication of VZV/Oka. EA exhibited a concentration-dependent reduction in the plaque formation of VZV/Oka with a 50% effective concentration $(EC_{50})$ of $464.14\;{\mu}g/ml$. The results of combination assay were evaluated by the combination index (CI) that was calculated by the multiple drug effect analysis. The combination of EA with acyclovir showed more potent synergism with CI values of $0.18{\sim}0.62$ for $50{\sim}90%$ effective levels than that of EA with vidarabine with CI values of $0.67{\sim}1.04$.

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Activity of Allyl Isothiocyanate and Its Synergy with Fluconazole against Candida albicans Biofilms

  • Raut, Jayant Shankar;Bansode, Bhagyashree Shridhar;Jadhav, Ashwini Khanderao;Karuppayil, Sankunny Mohan
    • Journal of Microbiology and Biotechnology
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    • v.27 no.4
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    • pp.685-693
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    • 2017
  • Candidiasis involving the biofilms of Candida albicans is a threat to immunocompromised patients. Candida biofilms are intrinsically resistant to the antifungal drugs and hence novel treatment strategies are desired. The study intended to evaluate the anti-Candida activity of allyl isothiocyanate (AITC) alone and with fluconazole (FLC), particularly against the biofilms. Results revealed the concentration-dependent activity of AITC against the planktonic growth and virulence factors of C. albicans. Significant (p <0.05) inhibition of the biofilms was evident at ${\leq}1mg/ml$ concentrations of AITC. Notably, a combination of 0.004 mg/ml of FLC and 0.125 mg/ml of AITC prevented the biofilm formation. Similarly, the preformed biofilms were significantly (p <0.05) inhibited by the AITC-FLC combination. The fractional inhibitory concentration indices ranging from 0.132 to 0.312 indicated the synergistic activity of AITC and FLC against the biofilm formation and the preformed biofilms. No hemolytic activity at the biofilm inhibitory concentrations of AITC and the AITC-FLC combination suggested the absence of cytotoxic effects. The recognizable synergy between AITC and FLC offers a potential therapeutic strategy against biofilm-associated Candida infections.

Antiherpetic Activities of Natural Quercetin Alone and in Combinations with Nucleoside Antiherpetic Agents (천연 Quercetin의 항허피스바이러스작용과 Nucleoside계 항허피스바이러스제와의 병용효과)

  • Kim, Young-So;Han, Seong-Sun
    • Korean Journal of Pharmacognosy
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    • v.30 no.2
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    • pp.151-157
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    • 1999
  • In order to find less toxic antiherpetic agents, the effect of natural quercetin on the plaque formation of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction assay. Quercetin caused a concentration-dependent reduction in the plaque formation of herpesviruses. It also exhibited more potent antiherpetic activity on HSV-1 with effective concentration $(EC_{50})$ of $18.7\;{\mu}g/ml$ than on HSV-2 with $EC_{50}$ of $24.5\;{\mu}g/ml$. The combined antiherpetic effects of quercetin with nucleoside antiherpetic agents, acyclovir and vidarabine, were examined on the multiplication of these two strains of herpesviruses in Vero cells by the combination assay. The results of combination assay were evaluated by the combination index (CI) that was calculated by the multiple drug effect analysis. The combinations of quercetin with acyclovir on HSV-1 and HSV-2 showed more potent synergism with CI values of $0.19{\sim}0.89$ for 50%, 70%, 90% effective levels than those with vidarabine with CI values of $0.43{\sim}1.46$.

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Vitamins E and C: Are They Synergistic in Protecting Liver Cells against Hepatic Ischimia and Reperfusion Injury\ulcorner (간장내 허혈 및 재관류시 Vitamin E와 C의 간세포 보호작용)

  • 이선미;김순애;조태순
    • Biomolecules & Therapeutics
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    • v.5 no.1
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    • pp.59-66
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    • 1997
  • This study was done to determine that vitamins I and C are synergistic in protecting liver cells during hepatic ischemia and repefusion. Rats treated with vitamins I and C were subjected to 60 min of hepatic ischemia and to 1 and 5 hr of reperfusion thereafter. Serum aminotransferase level and microsomal lipid peroxidation were markedly increased by ischemia/reperfusion. These increases were significantly attenuated by vitamins E, C or its combination. Hepatic wet weight-to-dry weight ratio was increased in ischemic group, but this increase was prevented by combination of vitamin I and C. Bile flow and cholate output were markedly decreased by ischemia/reperfusion and vitamin C alone and combination of vitamin I and C restored their secretion. Cytochrome P-450 content and aminopyrine N-demethylase activity were decreased by ischemia/ reperfusion and restored by vitamin C and combination of vitamin I and C to the level of sham-operated rat. Aniline p-hydroxylase activity was increased by ischemia/reperfusion and this increase was prevented by vitamin E. Our findings suggest that ischemia/reperfusion diminishes hepatic secretory and microsomal functions by increasing lipid peroxidation and vitamins I and C synergistically ameliorates these changes.

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Evaluation of Topical Drug Containing Solcoseryl and Micronomicin on Surgical Wound in Mice

  • Chung, Kae-Jong;Chang, Man-Sik;Chun, Jong-Ok;Chun, Jae-Kwang;Kim, Sung-Chul;Park, Wahn-Soo;Lee, Hyang-Woo
    • Biomolecules & Therapeutics
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    • v.2 no.1
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    • pp.23-27
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    • 1994
  • Wound healing and antibacterial effects of solcoseryl-micronomicin combination gel on an open wound were studied in mice. A simple model was designed for assessing the effects. Using the model, we compared the efficacy of a combined topical gel of solcoseryl and micronomicin with those gels of solcoseryl or micronomicin alone. From the results of our experiment, the wound healing effect of open wounds by treatment with the combination gel was significantly enhanced when compared with those by treatment with solcoseryl gel or micronomicin gel alone. And the antibacterial effect of the combination gel was higher than those of solcoseryl gel or micronomicin gel alone.

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Synergism of Cytotoxicity Effects of Triptolide and Artesunate Combination Treatment in Pancreatic Cancer Cell Lines

  • Liu, Yao;Cui, Yun-Fu
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.9
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    • pp.5243-5248
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    • 2013
  • Background: Triptolide, extracted from the herb Tripteryglum wilfordii Hook.f that has long been used as a natural medicine in China, has attracted much interest for its anti-cancer effects against some kinds of tumours in recent years. Artesunate, extracted from the Chinese herb Artemisia annua, has proven to be effective and safe as an anti-malarial drug that possesses anticancer potential. The present study attempted to clarify if triptolide enhances artesunate-induced cytotoxicity in pancreatic cancer cell lines in vitro and in vivo. Methods: In vitro, to test synergic actions, cell viability and apoptosis were analyzed after treatment of pancreatic cancer cell lines with the two agents singly or in combination. The molecular mechanisms of apoptotic effects were also explored using qRT-PCR and Western blotting. In vivo, a tumor xenograft model was established in nude mice, for assessment of inhibitory effects of triptolide and artesunate. Results: We could show that the combination of triptolide and artesunate could inhibit pancreatic cancer cell line growth, and induce apoptosis, accompanied by expression of HSP 20 and HSP 27, indicating important roles in the synergic effects. Moreover, tumor growth was decreased with triptolide and artesunate synergy. Conclusion: Our result indicated that triptolide and artesunate in combination at low concentrations can exert synergistic anti-tumor effects in pancreatic cancer cells with potential clinical applications.

Antiviral Effect of Water Soluble Substance from Elfvingia applanata Alone and in Combinations with Interferons on Vesicular Stomatitis Virus (Indiana Serotype) (잔나비걸상 수용성 물질의 Vesicular Stomatitis Virus (Indiana Serotype)에 대한 항바이러스작용과 Interferon과의 병용효과)

  • Kim, Young-So;Eo, Seong-Kug;Han, Seong-Sun
    • Korean Journal of Pharmacognosy
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    • v.30 no.3
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    • pp.244-249
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    • 1999
  • In order to find less toxic antiviral agents from Basidiomycetes, EA, the water soluble substance, was prepared from the carpophores of Elfvingia applanata(Pers.) Karst. Antiviral activity of EA against vesicular stomatitis virus [Indiana serotype, VSV(IND)] was examined in Vero cells using plaque reduction assay in vitro. And the combined antiviral effects of EA with interferon (IFN) alpha or gamma were examined on the multiplication of VSV(IND). EA caused a concentration-dependent reduction in the plaque formation of VSV(IND) with 50% effective concentration $(EC_{50})$ of $104.02\;{\mu}g/ml$. The results of combination assay were evaluated by the combination index (CI) that was analysed by the multiple drug effect analysis. All cases of the combination of EA with IFN alpha or IFN gamma showed potent synergism with CI values of $0.38{\sim}0.52$ for $50{\sim}90%$ effective levels.

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Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy

  • Jae-Sung Park;Min Ju Lee;Seong Bin Jo;Young Ae Joe
    • Biomolecules & Therapeutics
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    • v.31 no.1
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    • pp.1-15
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    • 2023
  • Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.