• BMB Reports
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• 제36권1호
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• pp.43-48
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• 2003

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identified, as well as their attendant concepts, including oncogenes, tumor suppressor genes, cell cycle biochemistry, hypotheses of metastasis, angiogenesis, etc. While all these "hallmarks" are well known, two important concepts, with their associated scientific observations, have been generally ignored by many in the cancer research field. The objective of the short review is to highlight the concept of the role of human adult pluri-potent stem cells as "target cells" for the carcinogenic process and the concept of the role of gap junctional intercellular communication in the multi-stage, multi-mechanism process of carcinogenesis. With these two concepts, an attempt has been made to integrate the other well-known concepts, such as the multi-stage, multi-mechanisn or the "initiation/promotion/progression" hypothesis; the stem cell theory of carcinogenesis; the oncogene/tumor suppression theory and the mutation/epigenetic theories of carcinogenesis. This new "integrative" theory tries to explain the well-known "hallmarks" of cancers, including the observation that cancer cells lack either heterologous or homologous gap junctional intercellular communication whereas normal human adult stem cells do not have expressed or functional gap junctional intercellular communication. On the other hand, their normal differentiated, non-stem cell derivatives do express connexins and express gap junctional intercellular communication during their differentiation. Examination of the roles of chemical tumor promoters, oncogenes, connexin knock-out mice and roles of genetically-engineered tumor and normal cells with connexin and anti-sense connexin genes, respectively, seems to provide evidence which is consistent with the roles of both stem cells and gap junctional communication playing a major role in carcinogenesis. The integrative hypothesis provides new strategies for chemoprevention and chemotherapy which focuses on modulating connexin gene expression or gap junctional intercellular communication in the premalignant and malignant cells, respectively.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 2002년도 학술대회지
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• pp.317-334
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• 2002

Ginsenosides are metabolized (deglycosylated) by intestinal bacteria to active forms after oral administration. 20(S)-Protopanaxadiol $20-O-{\beta}-D-glucopyranoside$ (M1) and 20(S)-protopanaxatriol (M4) are the main intestinal bacterial metabolites (IBMs) of protopanaxadiol- and protopanaxatriol-type glycosides. M1 was selectively accumulated into the liver soon after its intravenous (i.v.) administration to mice, and mostly excreted as bile; however, some M1 was transformed to fatty acid ester (EMl) in the liver. EM1 was isolated from rats in a recovery dose of approximately $24mol\%.$ Structural analysis indicated that EM1 comprised a family of fatty acid mono-esters of M1. Because EM1 was not excreted as bile as Ml was, it was accumulated in the liver longer than M1. The in vitro cytotoxicity of M1 was attenuated by fatty acid esterification, implying that esterification is a detoxification reaction. However, esterified M1 (EM1) inhibited the growth of B16 melanoma more than Ml in vivo. The in vivo antitumor activity paralleled with the pharmacokinetic behavior. In the case of M4, orally administered M4 was absorbed from the small intestine into the mesenteric lymphatics followed by the rapid esterification of M4 with fatty acids and its spreading to other organs in the body and excretion as bile. The administration of M4 prior to tumor injection abrogated the enhanced lung metastasis in the mice pretreated with 2-chloroadenosine more effectively than in those pretreated with anti-asialo GMl. Both EM1 and EM4 did not directly affect tumor growth in vitro, whereas EM1 promoted tumor cell lysis by lymphocytes, particularly non-adherent splenocytes, and EM4 stimulated splenic NK cells to become cytotoxic to tumor cells. Thus, the esterification of IBM with fatty acids potentiated the antitumor activity of parental IBM through delay of the clearance and through immunostimulation. These results suggest that the fatty acid conjugates of IBMs may be the real active principles of ginsenosides in the body.

• Asian Pacific Journal of Cancer Prevention
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• 제16권2호
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• pp.531-535
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• 2015

Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenesis, which was associated with invasion and metastasis. The grape seed proanthocyanidins (GSPs) had attracted much attention as a potential bioactive anti-carcinogenic agent. However, GSPs regulation of VM and its possible mechanisms in a triple-negative breast cancer cells (TNBCs) remain not clear. Therefore, we examined the effect of GSPs on VM information in HCC1937 cell model. In this study, we identified the VM structure via the three-dimensional (3D) matrix in vitro. Cell viability was measured using the CCK8 assay. The effects of GSPs on human triple-negative breast cancer cells (TNBCs) HCC1937 in terms of related proteins of VM information were determined using western blot analysis. In vitro, the tubular networks were found in highly invasive HCC1937 cells but not in the non-invasive MCF-7 cells when plated on matrigel. The number of vascular channels was significantly reduced when cells were exposed in GSPs ($100{\mu}g$/ml) and GSPs ($200{\mu}g/mL$) groups (all p<0.001). Furthermore, we found that treatment with GSPs promoted transition of the mesenchymal state to the epithelial state in HCC1937 cells as well as reducing the expression of Twist1 protein, a master EMT regulator.GSPs has the ability to inhibit VM information by the suppression of Twist1 protein that could be related to the reversal of epithelial-to-mesenchymal (EMT) process. It is firstly concluded that GSPs may be an p otential anti-VM botanical agent for human TNBCs.

• The Korean Journal of Physiology and Pharmacology
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• 제12권5호
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• pp.225-230
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• 2008

Netrins are secreted molecules and involved in axon guidance, cell migration and tumor development. Recent studies revealed that netrins perform novel functions in such processes as epithelial development and angiogenesis without operating through the classical netrin receptors, DCC (Deleted in Colorectal Cancer) and Unc5h. In the present study, we investigated the roles of netrin-1 and its receptors in cell spreading of human glioblastoma cells, and found that netrin-1 haptotactically enhanced fibronectin-induced cell spreading and focal adhesion formation in U373 glioblastoma cells. Netrin-1 binding to the U373 cell membrane was blocked by an antibody against ${\alpha}v$ integrin subunit, but not by an anti-DCC or anti-Unc5h antibody. In addition, enhancement of the fibronectin response by netrin-1 was abrogated by a function blocking antibody against integrin ${\alpha}v{\beta}3$. Since the ${\alpha}v$ subunit of the integrin family plays an important role in the pathophysiological aspects of cell migration, including tumor angiogenesis and metastasis, our data provide important insight into the molecular mechanism of netrin function.

• Biomolecules & Therapeutics
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• 제18권1호
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• pp.92-98
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• 2010

Breast cancer has been estimated as one of the most common causes of cancer death among women. The major cause of death from breast cancer is the metastatic spread of the disease from the primary tumor to distant sites in the body. Lycopene is one of the major carotenoids in fruits and vegetables including tomatoes. Epidemiological studies have shown that the dietary intake of lycopene is associated with decreased risk of cancer. Although mounting evidence shows the chemopreventive effect of lycopene, the role of lycopene in the prevention of metastatic potential of breast cancer has not been determined yet. In the present study, we investigated the inhibitory effect of lycopene on invasive and migratory phenotypes of two highly aggressive breast cancer cell lines, H-Ras-transformed MCF10A human breast epithelial cells (H-Ras MCF10A) and MDA-MB-231 human breast cancer cells. Here, we report that lycopene significantly inhibits invasion and migration as well as proliferation of H-Ras MCF10A and MDA-MB-231 cells. This study suggested an in vitro anti-cancer and anti-metastatic potential of lycopene. We also showed that activations of ERKs and Akt were inhibited by lycopene in H-Ras MCF10A cells, suggesting that the ERKs and Akt signaling pathways may be involved in lycopene-induced anti-proliferative and/or anti-invasive/migratory effects in these cells. Taken in conjunction with the fact that breast cancer metastasis is one of the most lethal malignancies in women, our findings may provide useful information for the application of lycopene in establishing strategy to prevent the metastatic breast cancer.

• BMB Reports
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• 제40권6호
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• pp.1069-1076
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• 2007

Cancer cells, characterized by local invasion and distant metastasis, are very much dependant on the extracellular matrix. The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. In this study, we reported the effects of disulfiram, a clinically used anti-alcoholism drug, on tumor invasion suppression, as well as its effects on the activity of MMP-2 and MMP-9 in human osteosarcoma cells (U2OS). Disulfiram has been used for alcohol aversion therapy. However, recent reports have shown that disulfiram may have potential in the treatment of human cancers. Herewith, we showed that the anti-tumor effects of disulfiram, in an invasion assay using U2OS cells and that disulfiram has a type IV collagenase inhibitory activity that inhibits expression of genes and proteins responsible for both cell and non-cell mediated invasion on pathways. In conclusion, disulfiram inhibited expression of MMP-2 and MMP-9 and it regulated the invasion of human osteosarcoma cells. These observations raise the possibility of disulfiram being used clinical for the inhibition of cancer invasion.

• 생명과학회지
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• 제16권6호
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• pp.964-971
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• 2006

기질의 침윤과 전이를 특징으로 하는 악성종양 세포는 세포외 기질이나 기저막에 의존적으로 작용한다. 세포외 기질을 분해하는 효소인 matrix metalloproteinase (MMP) 계들의 발현 및 활성증가는 대부분의 악성종양세포에서 전이와 침윤을 촉진시킨다. MMP family 가운데 특히 type IV collagenase 활성을 지닌 MMP-2와 MMP-9은 세포외기질의 중요한 구성분인 collagen, fibronectin을 분해하는 특성을 가지며 암 전이를 용이하게 하는 주요한 효소로 잘 알려져 있다. 본 연구에서는 항암후보물질인 disulfiram이 골 육종 (U20S), 신장암 (Caki-1) 및 자궁암 (Caski) 세포에서 MMP-2와 MMP-9의 효소활성 및 발현억제에 대해 조사하였다. MTT assay를 이용하여 disulfiram에 대한 암세포 viability 실험에서는 disulfiram이 암세포의 viability를 저해하였다. 또한 zymography, western blot 및 RT-PCR 등을 이용한 type IV collagenase의 활성 및 발현 실험에서 disulfiram은 type IV collagenase의 활성을 비롯하여 단백질 및 mRNA 발현을 억제시키는 것을 확인하였다. 따라서 disulfiram이 MMP-2와 MMP-9의 활성 및 발현 억제 기전을 통하여 골 육종, 신장암 및 자궁경부암 세포의 작용을 억제한다는 연구 결과는 disulfiram이 각종 악성종양의 침윤과 전이를 억제 또는 방지하기 위한 치료물질로서 임상에서 활용할 수 있는 가능성을 보여준다.

• Journal of Acupuncture Research
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• 제31권4호
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• pp.81-97
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• 2014

Objectives : The purpose of this study is analyzing the current research methodology of pharmacopucture for the treatment of animal cancer models. Methods : Four electronic databases were searched for animal studies published from January 2000 to September 2014 onward using these search terms "cancer, anticancer, pharmacopuncture, beevenom". Selected articles were described about animal cancer models. The methods used to induce cancer and the outcome measures used to assess the effects of pharmacopuncture on animal cancer models were analyzed. Results : 37 articles were included. For producing animal cancer models BALB/C mice(n=22) and C57BL/6 mice(n=17) were selected. And intravenous injection of B16-F10 melanoma cells into tail vein(n=14) or intraperitoneal injection of sarcoma-180 cells(n=14) were frequently used to induce cancer. Various pharmacopunctures were injected into acupoints $CV_{12}(n=19)$, $ST_{36}(n=8)$, $BL_{18}(n=8)$ or peritoneal cavity(n=6), tumor site(n=2), tail vein(n=2). Outcome measures were categorized into anti-cancer, anti-metastasis, general condition, cytotoxicity, immune response, toxicity. Median Survival Time(MST) and increase of life span(ILS)(n=26) was frequently used for evaluating anti-cancer effects. And pulmonary colonization assay(n=13) was frequently used for evaluating anti-metastasis effects Conclusions : Based on these data, further research would be needed to ascertain the effectiveness of pharmacopuncture for treating cancer and broaden the range of clinical applications.

• 한국식품위생안전성학회지
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• 제31권1호
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• pp.59-66
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• 2016

Celastrol은 미역줄나무의 뿌리에서 얻은 추출물로 오래전부터 관절염 및 자가면역 같은 염증반응 질병들을 치료하기 위하여 쓰여져 왔다. 이외에도 많은 연구들에서 celastrol이 신경보호, 항산화 및 알츠하이머 치료에 사용될 수 있으며 특히, 암 치료에 효과적이라고 밝혀 졌다(Table 1). 따라서 많은 연구자들이 생리학적, 생화학적 및 면역학적 관점에서 celastrol의 항암효과를 규명하고자 노력을 기울이고 있으며, 다양한 관점에서 신호전달체계를 조절한다는 사실을 밝혀냈다(Fig. 1). 특히, celastrol은 $NF-{\kappa}B$를 억제함으로서 암의 발달 및 전이를 저해함을 물론, 암의 치료에 동반되는 면역 반응을 조절 할 수 있다(Fig. 2). 또한 세포사멸과 관계된 유전자들을 활성화 시키고, 항세포사멸 유전자들을 억제시킴으로서 세포 주기를 조절한다. 유전자 조절 외에도 heat shock protein과 같은 단백질의 변조와 자가소화작용(autophagy)를 유도한다. 이처럼 celastrol의 다양한 효과는 암의 성공적 치료에 한발 더 가까워지게 만든다. 이외에도 celastrol의 항 비만 효과가 알려지면서 향후 비만 및 비만과 연계된 암 환자들이 가질 수 있는 부작용, 오남용 및 비용절감 측면에서 좋은 결과를 나타낼 것이라 예상 된다. Celastrol의 다양한 기작이 밝혀짐에도 불구 하고 직접적인 결합 부위에 대한 연구 결과는 아직 없으며, 임상적용 하기에 앞서 다양한 동물모델 in vivo 실험이 필요하다. 또한 임상치료 시도에 있어 안전성을 확보 하기 위해서는 celastrol의 단기간 및 장기간의 효과에 대한 깊은 연구가 요구된다.

• 대한한의학회지
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• 제27권4호
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• pp.30-47
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• 2006

Objective : The present study is aimed to elucidate the effects of Cirsium japonicum var. ussuriense on immunomodulation and the potential as an herbal remedy for cancer treatment. Method : It was performed through measurement of effects Cirsium japonicum var. ussuriense extract (CJE) on NO production, NK cell cytotoxicity and cytokine gene expressions related with macrophage and NK cell activity. Result : 1. CJE did not show any direct cytotoxic effects on 7250, HT1080, Hep G2 and CT-26 cells. 2. CJE activated macrophages partially to product NO and up-regulated gene expressions for iNOS in RAW 264.7 cells. 3. CJE promoted cytotoxicity of NK cells against YAC-1 cells at higher concentration than 200 ${\mu}g/ml$. 4. CJE up-regulated gene expressions for $IL-1{\beta}$, IL-2, iNOS, $IFN-{\gamma}$ and $TNF-{\alpha}$ in mice splenocytes.　５. CJE inhibited lung tumor metastasis induced by CT-26 cell transplantation compared with the control group.　Conclusion : It could be concluded that CJE is an effective herbal drug for immune modulating and anti-cancer treatment by promoting activity of macrophages and NK cells.