• Title/Summary/Keyword: 면역항암제

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The Functional Role of Lysosomes as Drug Resistance in Cancer (항암제 내성에 대한 라이소좀의 역할)

  • Woo, Seon Min;Kwon, Taeg Kyu
    • Journal of Life Science
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    • v.31 no.5
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    • pp.527-535
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    • 2021
  • Lysosomes are organelles surrounded by membranes that contain acid hydrolases; they degrade proteins, macromolecules, and lipids. According to nutrient conditions, lysosomes act as signaling hubs that regulate intracellular signaling pathways and are involved in the homeostasis of cells. Therefore, the lysosomal dysfunction occurs in various diseases, such as lysosomal storage disease, neurodegenerative diseases, and cancers. Multiple forms of stress can increase lysosomal membrane permeabilization (LMP), resulting in the induction of lysosome-mediated cell death through the release of lysosomal enzymes, including cathepsin, into the cytosol. Here we review the molecular mechanisms of LMP-mediated cell death and the enhancement of sensitivity to anticancer drugs. Induction of partial LMP increases apoptosis by releasing some cathepsins, whereas massive LMP and rupture induce non-apoptotic cell death through release of many cathepsins and generation of ROS and iron. Cancer cells have many drug-accumulating lysosomes that are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. Lysosomal sequestration of hydrophobic weak base anticancer drugs can have a significant impact on their subcellular distribution. Lysosome membrane damage by LMP can overcome resistance to anticancer drugs by freeing captured hydrophobic weak base drugs from lysosomes. Therefore, LMP inducers or lysosomotropic agents can regulate lysosomal integrity and are novel strategies for cancer therapy.

Busulfan Inhibits PCNA Expression but Induces The Expression of pRB

  • 천영신;주학진;권득남;김진희
    • Proceedings of the KSAR Conference
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    • 2001.03a
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    • pp.21-21
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    • 2001
  • 일반적으로 세포는 방사능이나 항암제 등의 자극에 의해 DNA가 손상받았을 때 DNA를 합성하기 전, DNA변이를 복구하기 위해 cell cycle을 정지시키게 된다. pRB(retinoblatoma protein)는 이러한 cell cycle의 조절기작에서 중요한 역할을 담당하는 것으로 알려져 있다. G1기에서 S기로 진행하는 것을 조절하는 단백질인 pRB 은 E2F(cell cycle transcription factor)와 상호작용하여 cell cycle 진행에 필요한 전사활성을 억제, PCNA (proliferating cell nuclear antigen)의 합성을 저해한다. 또한, E2F와 결합된 pRB는 apoptosis를 제어하는 유전자를 조절하는 것으로 알려져 있다. Cell cycle에 영향을 미치는 항암제의 일종인 busulfan을 처리하면, 정소 내에 존재하는 대부분의 생식세포들은 사멸되고 spermatogonia만 남는 것으로 알려져 있다. 그러나 그 기작에 대해서는 자세히 연구된 바가 없다. 본 연구에서는 busulfan처리시 spermatogonial stem cell이 어떤 기작에 의해 손상받지 않고 유지되는지를 알아보고자 실험을 수행하였다. Busulfan을 처리한 마우스 (항암제 투여 후 5주)와 정상적인 13주령의 마우스의 정소로부터 각각 세포를 분리하였다. LSC (laser scanning cytometry)를 이용하여 처리군(busulfan treated mice)과 대조군(normal mature mice)에 대해 각각 DNA함량을 비교ㆍ분석한 결과 G0/G1(2N)에 머물러 있는 세포비율이 처리군에서 현저하게 증가했다 (79.3$\pm$5.5%:8.1$\pm$1.3%). Cell cycle의 G1/S check point인 pRB와 PCNA 발현을 Western blot과 면역조직학적인 방법(immunohisto-chemistry)을 이용하여 조사하였다 PCNA는 대조군과 비교해, 처리군에서 매우 낮은 수준으로 발현되었다. 면역염색된 정소단면을 살펴보면, 대조군에서는 모든 세정관에서 PCNA를 발현하는 세포가 높은 비율로 검출되었고, 처리군에서는 소수의 세정관에서 세포들이 낮은 수준으로 검출되었다. 반면에, pRB의 경우 PCNA와는 상반된 결과를 나타내어, 대조군에서는 거의 발현이 되지 않는 반면, 처리군에서는 대부분의 세정관내, 기저막을 따라 위치한 세포들에서 발현되었다. 이상의 결과는 busulfan에 의해 pRB의 인산화가 억제, pRB 와 결합된 E2F는 전사 활성이 억제되어, PCNA 합성을 저해하는 것으로 설명되어질 수 있다. 결론적으로, 인산화가 억제된 pRB (underphosphorylated RB protein)이 quiescent spermatogonial stem cell에서만 특이하게 발현하는 단백질이며, 이러한 pRB의 발현은 apoptosis를 제어하는 역할을 담당해 busulfan처리에 의해 손상받지 않고 남아있는 것으로 시사된다.

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Comparison of Anticancer Activities of Berberis koreana Extracts Obtained by Different Extraction Processes (추출 공정별 매자나무 추출물의 항암활성 비교)

  • Ha, Ji-Hye;Kwon, Min-Cheol;Seo, Yong-Chang;Choi, Woon-Yong;Chung, Eul-Kwon;Chung, Ae-Ran;Kim, Jin-Chul;Ahn, Ju-Hee;Lee, Hyeon-Yong
    • Korean Journal of Food Science and Technology
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    • v.42 no.2
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    • pp.233-239
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    • 2010
  • This study was conducted to examine the anticancer activities of Berberis koreana extracts according to different extraction processes. The highest extraction yield obtained was 8.26% following extraction by ultrasonification at 60 kHz and $60^{\circ}C$ followed by high pressure at 500MPa. Generally, the extracts from the ultrasonification process showed relatively low cytotoxicities against the human normal cell line, HEK293 showing as low as 15%. This extract inhibited the growth of the digestive related organs cell lines, human stomach adenocarcimoma cell and human epithelial adenocarcinoma cell by up to 80% when administered at 1.0 mg/mL, and showed 2.5-3.5 of selectivity. It was also found that this extract induced the production of nitric oxide levels as high $37.87\;{\mu}M$ from macrophages. For the in vivo experiment using ICR mice, the total serum IgG levels of mice treated with B. koreana extracts from ultrasonification extraction were increased by up to 57 ng/mL. The survival time of this group was longer than that of the other group after the injection of Sarcoma-180 and the increment of their body weights was also greatly suppressed. In addition, the extract showed the highest tumor inhibition activities, leading to a reduction of 78.47%. These results indicate that the highest activities of B. koreana associated with this extraction process can be significantly improved.

국내산 가시파래(Enteromorpha prolifera)로부터 수용성 다당의 추출 및 정제

  • 최용석;구재근;김풍호;하진환
    • Proceedings of the Korean Society of Fisheries Technology Conference
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    • 2000.10a
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    • pp.177-178
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    • 2000
  • 해조(seaweed)는 한국, 일본, 중국과 같은 아시아 지역에서 바다채소(sea vegetable로서 식용되어왔으며, 유럽에서는 주로 겔화제, 비료 등으로 사용해 왔다. 그러나 최근들어 해조류에 함유되어 있는 성분들의 영양학적 측면 뿐 만아니라 생리활성물질에 대한 관심이 고조되면서 항종양성, 항virus성, 면역력 증강, 항암작용, 다이어트식품 등의 다양한 연구가 발표되고 있다(Ito and Hori,1989). (중략)

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Production of Reactive Oxygen Species and Nitric Oxide by Anticancer Agents in Rat Polymorphonuclear Leukocytes (항암제에 의한 흰쥐 다형핵백혈구의 활성산소종(reactive oxygen species) 및 산화질소(nitric oxide)의 생성)

  • Kang, Dong-Joon;Song, Seung-Hee;Kim, Cheol-Ho;Lee, Sang-Kil;Kang, Chung-Boo
    • Journal of Veterinary Clinics
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    • v.26 no.1
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    • pp.8-16
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    • 2009
  • The production of reactive oxygen species (ROS) and nitric oxide (NO) by anticancer agents in rat polymorphonuclear leukocytes (PMN) was examined. PMN treated for short term (< or = 4 h) with cyclophosphamide, cisplatin, tamoxifen and doxifluridine, respectively, exhibited an enhanced respiratory burst upon formylmethionylleucy1-phenylalanine (FMLP) stimulation. In the long term (> 4h), the production of ROS was suppressed in a concentration-dependent manner. The production of superoxide anion (${O_2}^-$) from the FMLP-stimulated PMN was enhanced by the treatment (for 1 hr) of cyclophosphamide, cisplatin, tamoxifen and doxifluridine, respectively. While 1 hr-treatment with cyclophosphamide, cisplatin, tamoxifen, and doxifluridine, respectively, suppressed the production of NO from the FMLP-stimulated PMN, while 8 hr-treatment enhanced the production of NO. Neomycin suppressed chemiluminescence in cisplatin-, tamoxifen- and doxifluridine-pretreated PMN, however near suppression of chemiluminescence by ethanol and genistein was observed in PMN pretreated with these agents. Staurosporine and bisindolylmaleimide suppressed chemiluminescence in cisplatin- and doxifluridine- pretreated PMN. Wortmannin has shown a slight suppression in cyclophosphamide-, cisplatin- and tamoxifen-pretreated PMN, but a strong suppression in doxifluridine-pretreated PMN. Methionine strongly suppressed in cyclophosphamide and cisplatin-pretreated PMN. In conclusion, these results indicate that long term treatment of PMN with cisplatin and doxifluridine inhibit respiratory burst through protein kinase C (PKC) translocation, phospholipase C (PLC), D (PLD) and tyrosine phosphorylation kinase (TPK) activation. Tamoxifen inhibits respiratory burst through PLC, PLD, TPK. Cyclophosphamide inhibits respiratory burst through myeloperoxidase (MPO) activity.

A PCR Denaturing Gradient Gel Electrophoresis (DGGE) Analysis of Intestinal Microbiota in Gastric Cancer Patients Taking Anticancer Agents (PCR-DGGE를 통해 분석한 항암치료에 따른 장내 미생물 변화)

  • Yu, Sun Nyoung;Ahn, Soon Cheol
    • Journal of Life Science
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    • v.27 no.11
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    • pp.1290-1298
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    • 2017
  • Intestinal microbiota is an important factor in the development of immune defense mechanisms in the human body. Treatments with anticancer agents, such as 5-Fluorouracil, Cisplatin, and Oxaliplatin, significantly change the temporal stability and environment of intestinal bacterial flora. The anticancer treatment chemotherapy often depresses the immune system and induces side effects, such as diarrhea. This study investigated the effects anticancer agents have on the intestinal microbial ecosystems of patients with gastric cancer. An exploration of the diversity and temporal stability of the dominant bacteria was undertaken using a DGGE with the 16S rDNA gene. Researchers collected stool samples from patients zero, two and eight weeks after the patients started chemotherapy. After the treatment with anticancer agents, the bacteria strains Sphingomonas paucimobilis, Lactobacillus gasseri, Parabacteroides distasonis and Enterobacter sp. increased. This study focused on the survival of the beneficial microorganisms Bifidobacterium and Lactobacillus in the intestines of cancer patients. The administration of antigastric cancer agents significantly decreased Lactobacillus and Bifidobacterium populations and only moderately affected the main bacterial groups in the patients' intestinal ecosystems. The results showed the versatility of a cultivation independent-PCR DGGE analysis regarding the visual monitoring of ecological diversity and anticancer agent-induced changes in patients' complex intestinal microbial ecosystems.

Antitumor Effects of Duck′s Egg Oil on the Cancer Cells (청둥오리 압란유의 항암 효과)

  • 류병호;김민정;양승택
    • Journal of Life Science
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    • v.12 no.1
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    • pp.61-66
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    • 2002
  • This study were constructed to investigate effects of duck's egg oil on antitumor agent or a new natural immunomodulator. To obtained the aboved objectives, Duck's egg oil was purified the large scale from Duck. Duck's egg oil was accelerated the increasing reaction of mouse spleen cells, while inhibited to increase the YAC-cells. However, there is no significance the rate of CD4'/CD8'cell. The normal rate of CD4'-T and CD8'-T cells were accelerated the higher rate than that normal mouse group, and Duck's egg oil feeding mice showed a significant enhancement of expression of IL-2 receptors, an increase of numbers of CD4+ T cells, CD8+ T cells. Otherwise, Duck's egg oil stimulated the production of NO from peritoneal macrophages and the production of TNF-a and also significantly accelerated in the spleen mice. On the other hands, lung localization of B16F10 melanoma cells inhibited by Duck's egg oil. These results found that Duck's egg oil is useful new functional materials as antitumor agent or immunomodulator.

Experimental Studies on the Antitumor Effects of Jinryungtang Gagambang Extract (진령탕가감방의 항종양효과(抗腫瘍效果)에 관(關)한 실험적(實驗的) 연구(硏究))

  • Jeong, Jun-Tak;Moon, Goo;Moon, Suk-Jae
    • THE JOURNAL OF KOREAN ORIENTAL ONCOLOGY
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    • v.4 no.1
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    • pp.37-53
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    • 1998
  • The sprig of Jinryungtang Gagambang has been used for curing as a traditional medicine without any experimental evidence to support the rational basis for their clinical use. This experiment was carried out to evaluate the possible therapeutic or antitumoral effects of Jinryungtang Gagambang extract against cancer, and to study some mechanisms responsible for its effect. The cytotoxic and antitumor effects were evaluated on human cell liens (A549, hep3B, Caki-1, Sarcoma 180) after exposure to Jinryungtang Gagambang extract using in ILS, colony forming efficency and SRB assay which were regarded as a valuable method for cytotoxic and antitumor effects of unknown compound on tumor cell lines. The results obtained in this studies were as follows. 1. As a result of exposure to Jinryungtang Gagambang extract, the proliferation of A549, hep3B, Caki-1, good correlations were shown from the results of SRB assay and those of clogenetic assay. 2. The oral administration of Jinryungtang Gagambang extract showed significant effects of increase of MST(mean survival time) and ILS(increased life span) depending on the increasing concentration. 3. Against squamous cell carcinoma induced by MCA, Jinryungtang Gagambang decreased not only the frequency of tumor production but also the number and weight of tumors per tumor bearing mice(TBM). Jinryungtang Gagambang also significantly suppressed the development of 3LL cell-implanted tumors by frequency and their size, and some developed tumors were regressed by the continuous treatment of Jinryungtang Gagambang extract into TBM. 4. Jinryungtang Gagambang extract also increased NK cell activities. According to the above results, it could be suggested that Jinryungtang Gagambang extract has prominent antiutmor effect.

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버섯의 항암효과 -영자 균사체 다당류의 항종양 활성-

  • 이준우
    • Proceedings of the Korean Journal of Food and Nutrition Conference
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    • 1997.06b
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    • pp.13-14
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    • 1997
  • 영지의 약리효과는 triterpenoid계의 저분자와 polysaccharide인 고분자로 대별할 수 있다. 저분자 물질은 항염증작용, 항알러지작용, 간암세포 성장 억제작용, 혈압 강하작용, 혈소판 응집저해작용 등이 있으며, 고분자 물질은 혈압강하작용, 정혈작용, 고지혈증 개선작용, 혈당 강하작용, 면역 증강작용 및 항종양작용 등이 있는 것으로 알려졌다. 현재까지의 영지에 관한 연구는 주로 자실체에 대한 연구가 주류를 이루고 있으며 이들의 산지, 환경조건, 채집시기 및 실험자들에 따라 약리 효과 등에 많은 차이가 있다. 이들에 대한 효과가 영지의 대표적 약리효과라고 언급하기엔 부족한 점이 많으므로 약리효과가 우수하고 일관성이 있는 영지 유래 다당류를 얻기 위한 방법으로서는 균사체의 대량배양법 및 분리방법이 확립 되어야만 한다. 본 연구에서는 새로운 항암활성 다당류의 개발을 위해 국내 자생 영지를 채집하여 검색 및 계통적 분류를 행하였으며 분리된 균주의 최적 액체배양 조건, 다당류 분리 조건, 다당류의 물리화학적 특성 및 약리활성 등에 관한 연구를 실시하였다. 그 중 약리활성이 우수한 G- lucidum IY009 균주를 선발 하였다. 구조적 특징과 종양 면역 활성과의 관계 규명을 위해, G- lucidum IY009 배양균사체로부터 다당류를 T-AS, U-AS, M-AS, S 및 H로 분획 하였다. 추출조건에 따른 다당류 GLG의 수율은 열수 추출 분획이 2.98g/l로 가장 높았으며, U-AS및 T-AS에서 각각 2.32g/l, 2.07g/l이었다. GLG의 특성을 조사하기 위하여 수용성과 비수용성으로 분리한 결과 수용성 분획은 비수용성 분획보다 높은 당 함량을 나타냈으며, T-AS는 70.3%의 당과 7.8%의 단백질로 구성 되었다. GLG 대부분의 분획들은 60~93%의 glucose로 구성된 다당류 이었으며, 주로 $\beta$-glucose로 구성된 다당류 이었다. 아미노산은 Asp 및 Glu의 산성 아미노산과 Ala, Leu 등의 함량이 높게 나타났으며, 비알칼리 추출물에서 Ser과 Thr의 함량이 높게 나타났다. 다당류 T-AS는 평균 분자량이 2,000 kD와 12kD에서 주 peak를 나타냈으며, 수용성 분획의 평균 분자량은 12kD이고 비수용성 분획은 36~2,000 kD의 평균 분자량 분포를 갖는 것으로 나타났다. IR과 NMR 분석 결과 890 cm-1에서 흡수 peak를 나타내어 $\beta$-(1,3)0glucan과 $\beta$-(1,6)-glucan의 구조를 갖는 다당류로 확인 되었다. T-AS 분획은 C:H:O:N의 함량비가 38.9:5.7:49.6:1.84%이며, 이 물질의 융점은 163 $^{\circ}C$로 연한 갈색을 나타낸다. 분리된 GLG의 항암활성 기전 규명을 위해, in vivo 항암실험, 항보체 활성능, 항체 생성능, serum protein 분비능, 대식세포의 탐식능과 활성능 및 세포간 물질 분비 등의 상관관계를 조사하였다. 다당류 GLG 분획물들 가운데 항보체의 활성이 높았던 분획은 sarcome 180에 대한 항암 활성이 높게 나타났다. 다당류 T-AS의 보체 활성화 기작은 classical과 alternative complement pathway의 양 경로를 통해 활성화 되었다. T-AS 분획은 mouse내의 특정 혈청단백을 증가시켰으며, 항체 생성능의 증가가 관찰되어 effect T 세포의 활성화가 나타나고 있음을 알 수 있었다. T-AS는 생체내 투여시에 대식세포의 탐식능이 증진되었으며, 대식세포 기능 저해제에 의한 대식세포의 기능 저해 현상이 회복되었다. 이와 같은 결과들로부터, T-AS의 항암 활성은 활성화된 보체 성분 및 당 수용체들이 존재하는 대식세포의 개입을 시사한다.

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Anti-cancer Effects and Molecular Mechanisms of Withaferin A (Withaferin A의 다양한 항암 효과 및 분자생화학적 기전)

  • Woo, Seon Min;Min, Kyoung-Jin;Kwon, Taeg Kyu
    • Journal of Life Science
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    • v.23 no.3
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    • pp.462-469
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    • 2013
  • Withaferin A is a steroidal lactone purified from the Indian medicinal plant Withania somnifera. It exhibits a wide variety of activities, including anti-tumor, anti-inflammation, and immunomodulation properties. In this review, we focused on the anti-cancer effects of withaferin A. Withaferin A inhibits cell proliferation, metastasis, invasion, and angiogenesis in cancer cells. Furthermore, it sensitized irradiation, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-, and doxorubicin-mediated apoptosis. The results showed that multiple mechanisms were involved in withaferin A-mediated anti-cancer effects. First, withaferin A increased intracellular reactive oxygen species (ROS) production and induced ER stress- and mitochondria-mediated apoptosis. Second, withaferin A inhibited the signaling pathways (Jak/STAT, Akt, Notch, and c-Met), which are important in cell survival, proliferation, and metastasis. Third, it induced apoptosis and inhibited cancer cell migration through the up-regulation of prostate apoptosis protein-4 (Par-4). Finally, withaferin A up-regulated pro-apoptotic protein expression levels through the inhibition of proteasome activity. Our findings suggested that withaferin A is a potential, potent therapeutic agent.