• Title/Summary/Keyword: synergistic inhibition

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APOPTOTIC EFFECT IN COMBINATION OF CYCLOSPORIN A AND TAXOL ON ORAL SQUAMOUS CELL CARCINOMA CELL LINE THROUGH THE PI-3 KINASE/AKT1 PATHWAY (구강 편평세포암종 세포주에서 Cyclosporin A와 Taxol 투여시 PI-3 kinase/Akt1 Pathway에 의한 세포사멸 병용효과)

  • Kim, Kyu-Young;Lee, Jae-Hoon
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.33 no.5
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    • pp.426-436
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    • 2007
  • Oral cancer take up 2-6% of all carcinomas and squamous cell carcinoma, which is the most common type in oral cancer, has a poor prognosis due to its high metastasis and recurrence rates. In treating oral cancer, chemotherapy to the primary, metastasized and recurrent lesion is a very important and useful treatment, even though its widespread usage is limited due to high general toxicity and local toxicity to other organs. Taxol, a microtubule stabilizing agent, is an anticancer drug that induces cell apoptosis by inhibiting depolymerization of microtubules in between the metaphase and anaphase of the cell mitosis. Recently, its effectiveness and mechanism on various tumor has been reported. However, not much research has been done on the application of Taxol to oral squamous cell carcinoma. Cyclosporin A, which is an immunosuppressant, is being used on cancers and when co-administered with Taxol, effectiveness of Taxol is enhanced by inhibition of Taxol induced multidrug resistance. In this study, Cyclosporin A with different concentration of Taxol was co-administered to HN22, the oral squamous cell carcinomacell line. To observe the cell apoptosis and the mechanisms that take part in this process, mortality evaluation of tumor cell using wortmannin, c-DNA microarray, RT-PCR analysis, cytometry analysis and western blotting were used, and based upon the observation on the effect and mechanism of the agent, the following results were obtained: 1. The HN22 cell line viability was lowest when $100{\mu}M$ of Wortmannin and $5{\mu}g/ml$ of Taxol were co-administered, showing that Taxol participates in P13K-AKT1 pathway. 2. In c-DNA microarray, where $1{\mu}g/ml$ of cyclosporine A and 3mg/ml of Taxol were co-administered, no up regulation of AKT1, PTEN and BAD c-DNA that participate in cell apoptosis was observed. 3. When $1{\mu}g/ml$ of Cyclosporin A was applied alone to HN22 cell line, no difference was found in AKT1, PTEN and BAD mRNA expression. 4. Increased AKT1, mRNA expression was observed when $3{\mu}g/ml$ of Taxol was applied alone to HN22 cell line. 5. When $1{\mu}g/ml$ of Cyclosporin A and Taxol($3{\mu}g/ml\;and\;5{\mu}g/ml$) were co-administered to HN22 cell line, PTEN mRNA expression increased, whereas AKT1 and BAD mRNA decreased. 6. As a result of cytometry analysis, in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration, increased Annxin V was observed, which shows that apoptosis occurred by deformation of plasma membrane. However, no significant difference was observed with vary ing concentration. 7. In western blot analysis, no caspase 3 was observed in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration. From the results of this study, it can be concluded that synergistic effect can be observed in combination therapy of Taxol and Cyclosporin A on oral squamous cell carcinoma cell line, where decreased activity of the cell line was observed. This resulted in decreased AKT1 and BAD mRNA and increased PTEN mRNA expression and when wortmannin and Taxol were co-administered, the viability decreased which confirms that Taxol decreases the viability of tumor cell line. Hence, when Taxol and cyclosporine A are co-administered, it can be assumed that cell apoptosis occurs through AKt1 pathway.

Prevention of thromboembolism with ticlopidine and aspirin after cardiac valve replacement (심장변막치환후 Ticlopidine과 Aspirin의 혈전방지 효과)

  • Kim, Gwang-Taek;Kim, Hak-Je;Kim, Hyeong-Muk
    • Journal of Chest Surgery
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    • v.19 no.1
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    • pp.35-42
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    • 1986
  • Prevention of thrombombolism after rosthetic cardiac valve replacement is essential for the patients. About 90% of patients are free of major and minor thromboembolic complications 5 year after replacement of cardiac valves with prosthetic devices when they are under control of anticoagulant therapy. Ticlopidine is a drug that alter platelet function to have an antithrombotic effect. It is an antiaggregating agent which inhibits primary platelet function to have an antithrombotic effect. It is an antiaggregating agent which inhibits primary platelet aggregation induced by ADP and increases the production of prostaglandin $D_{2}$. Aspirin in small doses inhibits platelet synthesis of prostaglandins by irreversibly blocking the enzyme cyclo-oxygenase. Platelet secretion and aggregation are impaired with Ticlopidine and Aspirin. the thromboembolic event sof 54 patient s who were treated with Ticlopidine and Aspirin after cardiac valve replacement were evaluated and compared with that of 79 patients who were treated with Wafarin and Aspirin after the same type of operation. The follow-up period ranged from 4 to 110 months (mean of 48 months). there were 11 major thromboembolic episodes including three deaths in the warfarin goup during mean follow-up period of 56 months. two cases of CVA and one hemoarthrosis were noted due to overdose of Warfarin. Inticlopidine group, there was only one fatal thromboembolic epdisode three month after mitral valve replacement during mean follow-up period of 18 months. Two episodes of hypermenorrhea resulting anemia ere noted in the ticlopidine group. We measured the parameters of platelet function in aggreagation curve of platelet with platelet aggregometer (chrono-log Aggregometer, Model No. 430) Aggregation test was performed with three final concentrations of epinephrine in 10 uM/L, ADP in 5uM/L. 28 patients with prosthetic cardiac valves and 35 healthy volunteers were subgrouped as follows to analyze the effect of antithrombotic drugs used. Group I ; 11 patients treated with 250-500 mg of ticlopidine and 0.5gm of Aspirin as a daily single dose after cardiac valve replacement (14 St. Jude Medical and 1 Carpentier-Edwards, 9 patients with atrial fibrillation among them) Group II ; 10 patients treated with 3-5 mg of Warfarin and 0.75 gm of Aspirin daily to prolong prothrombin time around 20 seconds for more than 6 months and single Aspirin dose was maintained afterward as a life-long regimes(3 St. Jude Medical, 1 Hall-Kaster and 7 Carpentier-Edwards valve, 9 patients in atrial fibrilation). Group III ; 7 patients who quit anticoagulant treatment (Warfarin + Aspirin) 6-12 months after the regime as group II (3 St. Jude Medical. 1 bjork-Shiley, 1 Hall-Kaster, 3 Carpentier-Edwards valve, 2 of them are with atrial fibrillation). Group IV ; 35 healthy vounteers (28 males and 7 females). The following results were obtained. 1. The mean maximal platelet aggregability in Group I induced by 10uM/L epinephrine was 15.6%, and 17.5 and 18.7% in BM in proportion to the induction by 5 and 10 uM/L ADP. 2. The mean maximal platelet aggregability in Group II induced by 10uM/L epinephrine was 16.5%, and 27.4 and 44.7% in BM in proportion to the induction by 5 and 10uM/L ADP. 3. The mean maximal platelet aggregability in group III induced by 10uM/L epinephrine was 65%, and 56.5 and 51.8% in BM in proportion to the induction by 5 and 10 uM/L ADP. 4. The mean maximal platelet aggregability in the normal subjects induced by 10 uM/L epinephrine was 64%, and 65 and 69% in Bm inproportion to the induction by 5 and 10 uM/L ADP. 5. Reversible change of platelet aggregation curve induced by 5 and 10uM/L was noted all of the patients in Group I. conclusion : Ticlopidine is an antiaggregating agent which inhibits primary platelet aggregation induced by ADP, and increases the production of prostaglandin $D_{2}$. Ticlopidine and Aspirin produced a significant inhibition of platelet in the presence of ADP and epinephrine in our study. Acccording to our brief experience, 250 mg of ticlopidine and low dose of Aspirin resulted synergistic superior effect to each drug alone in prevention of thromboembolism after prosthetic cardiac valve replacement.

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Effects of Schisandrae Fructus and Corni Fructus Extracts on the Proliferation and Expression of Prostatic Hyperplasia-inducing Factors in Dihydrotestosterone-stimulated LNCaP Human Prostate Carcinoma Cells (오미자와 산수유 추출물이 dihydrotestosterone가 처리된 LNCaP 인간 전립선 암세포의 증식 및 전립선 비대 유발 인자 발현에 미치는 영향)

  • Kim, Min Yeung;Ji, Seon Yeong;Hwangbo, Hyun;Lee, Hyesook;Kim, Tae Hee;Yoon, Seonhye;Kim, Hyun Jin;Kim, Sung Yeon;Kim, Tae Jung;Kim, Min Ji;Jung, Ha Eun;Choi, Yung Hyun
    • Journal of Life Science
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    • v.31 no.10
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    • pp.885-897
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    • 2021
  • Schisandrae Fructus (SF) and Corni Fructus (CF) have been used for a long time for the prevention and treatment of various diseases. Although reports have highlighted the possibility of inhibiting the onset and progression of benign prostatic hyperplasia (BPH), studies on related mechanisms are still lacking. In this study, we investigated the potential of SF and CF in improving BPH by using a dihydrotestosterone (DHT)-induced in vitro BPH model using LNCaP prostate carcinoma cells. According to our results, water and ethanol extracts of SF and CF significantly inhibited the proliferation of LNCaP cells by DHT treatment and markedly downregulated the expression of DHT-induced BPH biomarkers and growth factors. They also regulated the expression of apoptosis regulatory factors and significantly reduced DHT-mediated oxidative stress. In addition, the protective effect on major factors involved in the pathogenesis of BPH was more effective in the ethanol extract treatment group than in the water extract group. Furthermore, the improvement effect on BPH was higher in the 1:1 combined treatment group than in the ethanol extract alone treatment group of SF and CF, and 60% ethanol extracts showed a better effect than 40% ethanol extracts. Therefore, our findings demonstrate that SF and CF can protect against BPH by preventing the hyperproliferation of prostate cells through the inhibition of the androgen signaling pathway, which was correlated with their antioxidant activities. Therefore, SF and CF extracts may be useful in the clinical treatment of BPH, and the combination of these two extracts can be synergistic.