• 약학회지
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• 제49권1호
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• pp.38-43
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• 2005

The occurrence of resistance to chemotherapeutic drugs is a major problem for successful cancer treatment. This resistant phenotype of cancer cell frequently reveals a broad spectrum to structurally and/or functionally unrelated anticancer drugs, termed multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp), a transmembrane drug efflux pump, is a major mechanism of MDR. Accordingly, considerable effort has been directed towards to development of compounds that inhibit P-gp, reverse the MDR phenotype and sensitize cancer cells to conventional chemotherapy without undesired toxicological effects. In an effort to search for novel MDR reversal agent, we tested the cytotoxicity of paclitaxel, a well-known substrate of P-gp, against P-gp-expressing HCT15 and HCT15/CL02 human colorectal cancer cells in the presence or absence of benzotriazepin analogues, as well as against P-gp-negative A549 human non-small cell lung and SK-OV-3 human ovarian cancer cells in vitro. Among the compounds tested, the agents that have phenyl amide moiety at 3 position remarkably increased the cytotoxicity of paclitaxel against P-gp-expressing cancer cells, but not against P-gp-negative cancer cells. BTZ-15 and BTZ-16 at $4\;{\mu}M$ revealed similar MDR reversal activity to $10\;{\mu}M$ verapamil, a well-known MDR reversal agent.

• Archives of Pharmacal Research
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• 제19권4호
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• pp.286-291
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• 1996

Phenolic compounds are prevalent as toxins or environmental pollutants, but they are also widely used as drugs for various purpose including anticancer agent. A novel biphenolic compound, bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane (GERI-BPO02-A) was isolated from the fermentation broth of Aspergillus fumigatus F93 previously, and it has revealed cytotoxicity against human solid tumor cells. Its effective doses that cause 50% inhibition of cell growth in vitro against non-small cell lung cancer cell A549, ovarian cancer cell SK-OV-3, skin cancer cell SK-MEL-2 and central nerve system cancer cell XF498 were 8.24, 10.60, 8.83, $9.85\mug/ml$ respectively. GERI-BPO02-A has also revealed cytotoxicity against P-glycoproteinexpressed human colon cancer cell HCT15 and its multidrug-resistant subline HCT15/CL02, and its cytotoxicity was not affected by P-glycoprotein. We have also tested cytotoxicities of structurally related compounds of GERI-BPO02-A such as diphenylmethane, 1,1-bis(3,4dimethylphenyl)ethane, 2,2-diphenylpropane, 2-benzylpyridine, 3-benzylpyridine, $4,4^I-di-tert-butylphenyl$, bibenzyl, $2,2^I-dimethylbibenzyl$, cis-stilbene, trans-stilbene, 3-tert-butyl-4-hydroxy-5-methylphenyisulfide, sulfadiazine and sulfisomidine for studying of structure and activity relationship, and from these data we could suppose that hydroxyl group of GERI-BPO02A conducted important role in its cytotoxicity.

• The Korean Journal of Physiology and Pharmacology
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• 제21권5호
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• pp.465-474
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• 2017

The aim of this study was to determine the raising anticancer effects of resveratrol (Res) on paclitaxel (PA) in non-small cell lung cancer (NSCLC) cell line A549. The $10{\mu}g/ml$ of Res had no effect on human fetal lung fibroblast MRC-5 cells or on A549 cancer cells and the 5 or $10{\mu}g/ml$ of PA also had no effect on MRC-5 normal cells. PA-L ($5{\mu}g/ml$) and PA-H ($10{\mu}g/ml$) had the growth inhibitory effects in NSCLC cell line A549, and Res increased these growth inhibitory effects. By flow cytometry experiment, after Res ($5{\mu}g/ml$)+PA-H ($10{\mu}g/ml$) treatment, the A549 cells showed the most apoptosic cells compared to other group treatments, and after additional treatment with Res, the apoptosic cells of both two PA concentrations were raised. Res+PA could reduce the mRNA and protein expressions of COX-2, and Res+PA could reduce the COX-2 related genes of VEGF, MMP-1, MMP-2, MMP-9, $NF-{\kappa}B$, Bcl-2, BclxL, procollagen I, collagen I, collagen III and CTGF, $TNF-{\alpha}$, $IL-1{\beta}$, iNOS and raise the TIMP-1, TIMP-2, TIMP-3, $I{\kappa}B-{\alpha}$, p53, p21, caspase-3, caspase-8, caspase-9, Bax genes compared to the control cells and the PA treated cells. From these results, it can be suggested that Res could raise the anticancer effects of PA in A549 cells, thus Res might be used as a good sensitizing agent for PA.

• Tuberculosis and Respiratory Diseases
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• 제70권3호
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• pp.206-217
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• 2011

Background: Transcription factor FOXP3 characterizes the thymically derived regulatory T cells. FOXP3 is expressed by cancer cell itself and FOXP3 expression was induced by TGF-${\beta}$ treatment in pancreatic cancer cell line. However, the expression of FOXP3 expression is not well known in patients with lung cancer. This study was conducted to investigate the expression of FOXP3 in patients with lung cancer and to investigate the regulation of FOXP3 expression by the treatment of TGF-${\beta}$ and DNA methyltransferase inhibitor in lung cancer cell lines. Methods: FOXP3 expression in the tissue of patients with resected non-small cell lung cancer (NSCLC) was evaluated by immunohistochemistry. The regulation of FOXP3 expression was investigated by Western blot and RT-PCR after lung cancer cell lines were stimulated with TGF-${\beta}1$ and TGF-${\beta}2$. The regulation of FOXP3 expression was also investigated by RT-PCR and flow cytometry after lung cancer cell lines were treated with DNA methyltransferase inhibitor (5-AZA-dC). Results: FOXP3 expression was confirmed in 27% of patients with NSCLC. In NCI-H460 cell line, TGF-${\beta}2$ decreased FOXP3 mRNA and protein expressions. In A549 cell line, both TGF-${\beta}1$ and TGF-${\beta}2$ decreased FOXP3 mRNA and protein expressions. 5-AZA-dC increased FOXP3 mRNA expression in NCI-H460 and A549 cell lines. Moreover, 5-AZA-dC increased intracellular FOXP3 protein expression in A549 cell lines. Conclusion: It was shown that FOXP3 is expressed by cancer cell itself in patients with NSCLC. Treatment of TGF-${\beta}2$ and DNA methyltransferase inhibitor seems to be associated with the regulation of FOXP3 expression in lung cancer cell lines.

• 생명과학회지
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• 제23권11호
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• pp.1351-1359
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• 2013

${\beta}$-Ionone의 인체 비소폐암세포 A-549 cells (human non-small lung cancer A-549 cell)에 대한 anti-proliferative effect에 관한 연구를 수행하였다. A-549 cell에 다양한 농도의 ${\beta}$-ionone (1, 5, 10, and 15 ${\mu}M$)을 2, 4, 6일 간 처리하고, 배양 2일에 A-549 cell의 생육억제와 관련되는 biochemical marker를 측정하였다. ${\beta}$-Ionone은 A-549 cell 생육을 dose와 time 의존적으로 저해하였다. ${\beta}$-Ionone 배양 2일의 $IC_{50}$은 5.0 ${\mu}g/ml$이었다. ${\beta}$-Ionone은 농도 의존적으로 apoptosis를 유도하였다. ${\beta}$-Ionone은 p53, p21 및 Bax protein 수준을 증가시켰으나, Bcl-2 protein 발현은 억제시켰다. ${\beta}$-ionone은 cytosol cytochrome c 함량을 증가시켰고, caspase-9과 caspase-3 효소 활성증가를 유도하였다. 또한, ${\beta}$-ionone은 $cPLA_2$와 COX-2 protein level을 감소시켰다. 이와 같은 결과는 ${\beta}$-ionone의 A-549 cell에 대한 생육억제효과는 Bax와 Bcl-2 gene 발현을 reciprocal regulation하여 유도한 apoptosis와 $cPLA_2$ 및 COX-2 protein 발현 억제에 기인함을 의미한다.

• Tuberculosis and Respiratory Diseases
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• 제40권6호
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• pp.653-658
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• 1993

연구배경 : 최근 분자유전학의 진보로 인하여 암은 다단계의 복잡한 과정을 거쳐 발생됨이 밝혀졌으며, 이러한 단계는 크게 암유전자의 활성화와 종양억제 유전자의 비활성화로 구분하게 되었다. 본 연구는 p53 종양억제 유전자에 대하여 연구하였는데, 이는 p53 유전자의 변이는 현재까지 밝혀진 종양억제 유전자중 가장 광범위한 종류의 암에서 변이가 확인되고 있기 때문이다. 폐암은 우리나라에서 비교적 흔한 암이나 분자유전학적 발암기전은 아직 불분명하다. 본 연구에서는 폐암 발생에 있어 p53 유전자의 역할을 연구하고자 사람 폐암세포주를 대상으로 p53 유전자중 변이가 높은 비율로 발생되는 영역으로 알려진 exon 4-8에 대한 유전자 변이를 연구하였다. 방법 : 사람 폐선암 세포주인 PC-9와 PC-14 그리고 사람 소세포폐암 세포주인 H69를 대상으로 proteinase K에 의한 소화와 phenol-chloroform-ethanol 방법으로 genomic DNA를 추출하였다. 추출한 DNA를 p53 유전자중 exon 4-8 영역에 대한 primer를 사용하여 polymerase chain reaction(PCR)을 하여 각 exon에 대한 DNA를 증폭시킨 뒤 single strand conformation polymorphism(SSCP) 방법으로 전기영동과 자기방사기록을 하여 전기영동상 이동변화를 관찰하여 변이를 연구하였다. 결과 : 사람 폐선암세포주인 PC-9와 PC-14 에서는 exon 7에, 사람 소세포폐암 세포주인 H69에서는 exon 5에서 전기영동상 이동변화가 관찰되어 이 영역에 p53 유전자 변이가 있음이 인정되었다. 결론 : 대상으로 하엿던 3종류의 사람 폐암세포주 모두에서 p53 유전자의 변이가 확인된 것은 p53 종양억제 유전자의 변이가 비소세포 및 소세포 폐암 발생에 중요한 역할을 하고 있음을 시사하는 소견으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.5703-5707
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• 2015

Background: Medicinal plants, especially examples rich in polyphenolic compounds, have been suggested to be chemopreventive on account of their antioxidative properties. Melissa officinalis L. (MO), an aromatic and medicinal plant, is well known in thios context. However, toxicity against cancer cells has not been fully studied. Here, we investigated the selective anticancer effects of an MO extract (MOE) in different human cancer cells. Materials and Methods: a hydro-alcoholic extract of MO was prepared and total phenolic content (TPC) and total flavonoid content (TFC) were determined by colorimetric assays. Antioxidant activity was determined by DPPH radical scavenging activity. MTT assays were used to evaluate cytotoxicity of different doses of MOE (0, 5, 20, 100, 250, 500, $1000{\mu}g/ml$) towards A549 (lung non small cell cancer cells), MCF-7 (breast adenocarcinoma), SKOV3 (ovarian cancer cells), and PC-3 (prostate adenocarcinoma) cells. Results: Significant (P<0.01) or very significant (P<0.0001) differences were observed in comparison to negative controls at all tested doses ($5-1000{\mu}g/ml$). In all cancer cells, MOE reduced the cell viability to values below 33%, even at the lowest doses. In all cases, $IC_{50}$ values were below $5{\mu}g/ml$. The mean growth inhibition was 73.1%, 86.7%, 79.9% and 77.8% in SKOV3, MCF-7 and PC-3 and A549 cells, respectively. Conclusions: Our results indicate that a hydro-alcoholic extract of MO possess a high potency to inhibit proliferation of different tumor cells in a dose independent manner, suggesting that an optimal biological dose is more important than a maximally tolerated one. Moreover, the antiprolifreative effect of MO seems to be tumor type specific, as hormone dependant cancers were more sensitive to antitumoral effects of MOE.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.6963-6966
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• 2015

Background: During the past few years, Hesa-A, a herbal-marine mixture, has been used to treat cancer as an alternative medicine in Iran. Based on a series of studies, it is speculated that Hesa-A possesses special cytotoxic effects on invasive tumors. To test this hypothesis, we investigated the selective anticancer effects of Hesa-A on several cancer cell lines with different metastatic potential. Materials and Methods: Hesa-A was prepared in normal saline as a stock solution of 10 mg/ml and further diluted to final concentrations of $100{\mu}/ml$, $200{\mu}g/ml$, $300{\mu}g/ml$ and $400{\mu}g/ml$. MTT-based cytotoxicity assays were performed with A549 (lung non small cancer), MCF-7 (breast adenocarcinoma), SKOV3 (ovarian cancer), and PC-3 (prostate adenocarcinoma) cells. Results: All treated cancer cells showed significant (P<0.01) or very significant (P<0.0001) differences in comparison to negative control at almost all of the tested doses ($100-400{\mu}g/ml$). At the lower dose ($100{\mu}g/ml$), Hesa-A reduced cell viability to 66%, 45.3%, 35.5%, 33.2% in SKOV3, A549, PC-3 and MCF-7 cells, respectively. Moreover, at the highest dose ($400{\mu}g/ml$), Hesa-A resulted in 88.5%, 86.6%, 84.9% and 79.3% growth inhibition in A549, MCF-7, PC-3 and SKOV3 cells, respectively. Conclusions: Hesa-A exert potent cytotoxic effects on different human cancer cells, especially those with a high metastatic potential.

• 한국자원식물학회지
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• 제31권3호
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• pp.218-227
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• 2018

In this study, we investigated the effect of the extracts from Vaccinium oldhamii on cell proliferation and the regulatory mechanisms of cyclin D1 protein level in human cancer cells. The branch extracts from Vaccinium oldhamii (VOB) showed higher inhibitor effect against the cell growth than leave extracts (VOL) and fruit extracts (VOF) in human colorectal cancer, breast cancer, prostate cancer, non-small lung cancer, pancreatic cancer and liver cancer cells. In addition, VOB decreased cyclin D1 level at both protein and mRNA level. MG132 treatment attenuated VOB-mediated cyclin D1 downregulation. A point mutation of threonine-286 to alanine attenuated cyclin D1 degradation by VOB. In addition, the inhibition of nuclear export by leptomycin B (LMB) attenuated cyclin D1 degradation by VOB. But, the treatment of PD98059 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor), LiCl ($GSK3{\beta}$ inhibitor), LY294002 (PI3K inhibitor) or BAY 11-7082 ($I{\kappa}K$ inhibitor) did not affect VOB-induced cyclin D1 degradation. In conclusion, VOB induced cyclin D1 degradation through redistribution of cyclin D1 from the nucleus to cytoplasm via T286 phosphorylation of cyclin D1, which resulted in the inhibition of cancer cell proliferation.

• 대한수의학회지
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• 제49권1호
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• pp.1-8
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• 2009

The ubiquitin-proteasome mediated protein degradation pathway plays an important role in regulating both cell proliferation and cell death. Proteasome inhibitors are well known to induce apoptosis in various human cancer cell lines. We investigated the effect of combined treatment with proteasome inhibitor and TRAIL, and a possible mechanism of the enhancing apoptosis by the both treatment, on TRAIL-resistant non-small cell lung cancer. A549 cells were exposed to the N-Acetyl-Leu-Leu-Norleu-al (ALLN) as a proteasome inhibitor and then treated with recombinant TRAIL protein. In A549 cells under proteasome inhibition conditions by pretreatment with ALLN, TRAIL treatment significantly decreased cell viability compared to that ALLN and TRAIL alone treatment. Also, the both treatment induced cell damage through DNA fragmentation and p53 expression. In addition, the combined treatment of both markedly increased caspase-8 activation, especially the exposure for 2 h, and Bax expression and induced the dissipation of mitochondrial transmembrane potential in A549 cells. Taken together, these findings showed that proteasome inhibition by ALLN enhanced TRAIL-induced apoptosis via DNA degradation by activated P53 and mitochondrial transmembrane potential loss by caspase-8 activation and bax expression. Therefore, our results suggest that proteasome inhibitor may be used a very effectively chemotherapeutic agent for the tumor treatment, especially TRAIL-resistant tumor cell.