• Journal of Life Science
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• v.30 no.8
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• pp.661-671
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• 2020

The resistance of cancer cells to anti-cancer drugs is the leading cause of chemotherapy failure. The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been gradually extended to cancer treatment through combination with anti-cancer drugs. In the current study, we investigated whether NSAIDs including celecoxib (CCB), 2,5-dimethyl celecoxib (DMC), and ibuprofen (IBU) could enhance the cytotoxic effects of imatinib and TNF-related apoptosis inducing ligand (TRAIL) on human cancer cells. We found that the NSAIDs potentiated TRAIL and imatinib cytotoxicity against human hepatocellular carcinoma (HCC) cell lines SNU-354, SNU-423, SNU-449, and SNU-475/TR and against leukemic K562 cells with high level of CD44 (CD44^highK562), respectively. More specifically, CCB induced endoplasmic reticulum stress via up-regulation of ATF4/CHOP which is associated with the induction of autophagy against HCC and CD44^high K562 cells. NSAID-induced autophagic activity accelerated TRAIL cytotoxicity of HCC cells through up- and down-regulation of DR5 and c-FLIP, respectively. The NSAIDs also potentiated imatinib-induced cytotoxicity and apoptosis through down-regulation of markers in CD44^highK562 cells that express a stemness phenotype. Our results suggest that the ability of NSAIDs to induce autophagy could enhance the cytotoxicity of TRAIL and imatinib, leading to a reverse resistance to these drugs in the cancer cells. In conclusion, NSAIDs in combination with low-dose TRAIL or imatinib may constitute a novel clinical strategy that maximizes therapeutic efficacy of each drug and effectively reduces the toxic side effects.

• Journal of the Korean Society of Food Science and Nutrition
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• v.40 no.5
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• pp.619-624
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• 2011

Tea extract (TE) has been shown to have anti-tumor properties in a wide variety of experimental systems. We evaluated green tea extract (GTE) as a biochemical modulator for the antitumor activity of cisplatin and doxorubicin in the treatment of human lung cancer A549 cells. Cells were grown in RPMI-1640 medium supplemented with 10% (v/v) heat-inactivated fetal bovine serum and two antibiotics (100 units/mL penicillin and $100\;{\mu}g$/mL streptomycin). Two types of TE, epigallocatechin galate (EGCG) and GTE, were used in this experiment. The cells were seeded at $1{\times}10^4$ cells/well in the RPMI-1640 media with or without TE ($100\;{\mu}g$/mL) and then treated with different concentrations of doxorubicin ($0{\sim}14\;{\mu}g$/mL) or cisplatin ($0{\sim}35\;{\mu}g$/mL). After incubation in 5% $CO_2$ at $37^{\circ}C$ for 24 hr, cell viability was determined with a MTT assay. We used a Western blot to detect the influence of EGCG and GTE on the expression of p53 and caspase-3 genes in the A549 cells. A549 cell viability decreased to 15% with a $10\;{\mu}g$/mL concentration of cisplatin, and to 21% with a $8\;{\mu}g$/mL concentration of doxorubicin, as measured with the MTT assay. However, pre-treatment of the cells with EGCG ($100\;{\mu}g$/mL) or GTE ($100\;{\mu}g$/mL) resulted in decreased cell viability with $6\;{\mu}g$/mL of cisplatin and $4\;{\mu}g$/mL of doxorubicin. There was no apparent change in cell viability between EGCG or GTE administration in cisplatin- or doxorubicin-induced cytotoxicity in A549 cells. The levels of p53 and caspase-3 in the A549 cells increased with both EGCG and GTE treatment. We found that GTE could potentially affect cisplatin- or doxorubicin-induced cytotoxicity of A549 cells, which may be useful in the chemotreatment of cancer.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.15 no.4
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• pp.2189-2198
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• 2014

Paraquat (PQ) is a very effective and widely used herbicide that was commercially introduced in 1962. In this study, instead of using antioxidants like in the past, to inhibit the formation of PQ-induced ROS, we attempted to reduce the oxygen concentration by using non-lethal hypoxia therapy. Therefore, we studied the toxicity of PQ in vivo, analyzed the major effects of ROS on the targeted lung tissue and compared the results with the gross histological changes after the cell protective effect of non-lethal hypoxia therapy. In vivo studies demonstrated that low-concentration oxygen therapy (i.e., 10-12% oxygen) in rats administered with PQ was associated with a higher survival rate than in rats that received only PQ. In vivo non-lethal hypoxia treatment showed better survival and less lung tissue damage. Using a hypoxic/anaerobic incubator with integrated multifaceted molecular analysis, including MDA assay, glutathione assay, and SOD assay, we established an optimal, significantly reduced in vivo non-lethal hypoxia treatment by exploiting the PQ-induced cytotoxicity responses.

• Journal of the Korean Chemical Society
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• v.53 no.1
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• pp.34-41
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• 2009

A new series of hydrazone derivatives were synthesized from 4-(2-chloroethyl)semicarbazide and their antiproliferative activity against human brain (U251) and liver (Hepg2) carcinoma cell lines were evaluated. The hydrazone compounds are benzaldehyde (2a-2g), acetophenone (3a-3f), and 3-formylindole derivatives (4a-4d). Among the acetophenone derivatives, 3e (p-methoxy substituted) and 3f (p-nitro substituted) showed the highest cytotoxic activity against Hepg2 cell line (I$C_{50}$ = 6 and 8 $\mu$g/ml, respectively). Among the 3-formylindole derivatives, 4a (hydrazone of 3-formylindole itself) showed a pronounced cytotoxic activity against both U251 (I$C_{50}$ = 21 $\mu$g/ml) and Hepg2 (I$C_{50}$ = 7 $\mu$g/ml).

• Applied Biological Chemistry
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• v.49 no.3
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• pp.248-253
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• 2006

The present study describes the preliminary evaluation of the cytotoxicity from Gleditsiae Semen extracts. G. Semen was extracted with methanol, ethanol, and acetone, and then cytotoxic effect of these extracts was measured by the MTT reduction assay and phase-contrast microscopy on the HT-29 human colon carcinoma cells. Among these extracts, methanol extract showed the highest cytotoxic activity on the HT-29 cells. The methanol extract was further fractionated with n-hexane, diethyl ether, ethyl acetate, and water layer according to the degree of polarity. The water layer showed the highest inhibitory activity on the growth of HT-29 cells, but the other fractions indicated the low cytotoxic activity. In addition, water layer also showed the cytotoxic activity against SW620 human colon carcinoma cells. Based on these results, we suggest that extracts of G. Semen may contain bioactive materials and are potential candidates as chemotherapeutic agents against human colon carcinoma cells.

• Microbiology and Biotechnology Letters
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• v.30 no.2
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• pp.157-161
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• 2002

Drug resistance is one of the most significant impediments to successful chemotherapy of cancer. Multidrug-resistance (MDR) is characterized by decreased cellular sensitivity to anticancer agents due to the overexpression of P-glycoprotein. By employing adriamycin-resistance CL02 cancer cells, we undertook the screening for agents which were effective to multidrug-resistant cancer cells. As a result, a myxobacterial strain JW117 was selected for study since the solvent extract of cell mass of the strain was found to exhibit significant activity against the CL02 cancer cells. Cytotoxicity-guided chromatographic fractionation led to the isolation of phenalamides $A_2$ and $A_3$. The producing organism was identified as Myxococcus stipitatus by taxonomic comparison with type strains of Myxococcus sp. as well as its morphological and physiological characteristics. Phenalamides$ A_1$,$ A_2$ and $A_3$ were as active against drug-resistant cancer cells CL02 and CP70 as against the corresponding sensitive cells with $IC_{50}$ values ranging from 0.23~0.57 $\mu\textrm{g}$/ml.

• Journal of Life Science
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• v.22 no.9
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• pp.1224-1230
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• 2012

Cancer chemotherapy drugs command a large share of the market, and the development of new therapeutics with high efficacy and specificity is an active area of study. Recently, the development of cancer therapeutics from natural products targeting angiogenesis has drawn attention due to conventional chemotherapeutics showing serious side effects and resistance in cancer cells. In this study, we investigated the pharmacological efficacy of Gomisin A, an active ingredient of Schizandra chinensis baillon, on tumor growth and metastasis. Administration of Gomisin A at 10 and 100 ${\mu}g/ml$ reduced tumor growth in vivo by $80.5{\pm}8.1%$ and $96.2{\pm}2%$, respectively, compared with positive tumor controls. Treatment of Gomisin A in normal and various tumor cell lines did not exert significant toxicity. Mice treated with Gomisin A at a concentration of 10 and 100 ${\mu}g$/head showed a significant reduction in tumor-induced angiogenesis of $151{\pm}16.9%$ and $98.5{\pm}29.5%$, respectively. Furthermore, tumor metastasis analysis revealed that the administration of Gomisin A at a concentration of 10 and 100 ${\mu}g$/head inhibited tumor metastasis by $13.5{\pm}8.56%$ and $58.3{\pm}9.12%$, respectively. In addition, Gomisin A significantly decreased cell adhesion of the B16BL6 cells to the extracellular matrix. These results demonstrate that Gomisin A inhibits tumor growth via suppression of angiogenesis and tumor metastasis inhibition, without cellular toxicity. The pharmacological efficacy of Gomisin A suggests that it may be a potential candidate for the development of cancer drugs.

• The Journal of Internal Korean Medicine
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• v.25 no.3
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• pp.451-460
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• 2004

Objective : 황금의 유방암세포주에 대한 항암효과 및 기전에 대한 연구는 아직 미흡하며, 특히 에스트로젠리셉터를 가지지않은 유방암세포주인 MDA-MB-231에 대한 효과 및 기전에 대한 연구는 아직 발표된바 없어, 이에 대한 연구가 진행되었다. Methods : 인간 유방암세포주 MDA-MB-231 MTT assay를 이용 성장방해비율을 조사하였으며. FACS analysis를 이용 cell cycle analysis를 시행하였고, Western Blot Analysis 및 Annexin V analysis를 시행하였다. Results : MDA-MB-231에 대한 황금의 IC50는 180 ug/ml 이었으며 최대 세포성장억제효과는 $500{\mu}g/ml$로 한약재중 비교적 강한 세포독성을 보여 주었다. 유세포분석 에서 황금 $500{\mu}g/ml$의 농도를 72시간 투여한 경우 세포사멸(Sub Gl) 분율이 대조군의 1.7%에 비해 21%로 높아 현저한 용량의존적인 세포사멸현상을 보여주었으며, 세포사멸을 보다 명확히 규명할 수 있는 Annexin V analysis에서도 황금 $200{\mu}g/ml$농도일때 48시간에서 17%의 뚜렷한 세포사멸효과를 나타내었다. 한편 세포사멸촉진인자인 Bax, 세포사멸실행단백질인자인 caspase 3의 활성과 PARP의 분할은 세포사멸이 세포주기정지와 더불어 세포사멸의 과정에 p53이 관여함을 알 수 있다. 앞으로의 연구는 p53발현이 다른 세포주와 각 단백질의 억제제를 통해 인과적인 관련성을 즘 더 명확히 할 필요가 있어야 할 것으로 생각되어진다. Conclusion : 유방암의 예후에 있어 호르몬치료에 부적절함으로 인해 예후가 나쁜 에스트로젠리셉터 발현이 없는 유방암에 대해서도 황금이 탁월한 항암효과를 보여주고 있으며, 임상적으로 황금단독, 다른 항암약재와의 배합, 그리고 기존의 항암화학요법이나 방사선요법과의 병용투여를 통한 초기 및 진행된 유방암의 치료에 대한 새로운 접근의 실마리를 제공할 것으로 생각된다.

• Tuberculosis and Respiratory Diseases
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• v.59 no.1
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• pp.30-38
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• 2005

Background : Arsenic trioxide ($As_2O_3$) has been used to treat acute promyelocytic leukemia, and it induces apoptosis in a variety of solid tumor cell lines including non-small cell lung cancer cells. However, nonsteroidal antiinflammatory drugs (NSAID) can enhance tumor response to chemotherapeutic drugs or radiation. It was previously demonstrated that a combination treatment with $As_2O_3$ and sulindac induces the apoptosis of NCI-H157 human lung carcinoma cells by activating the caspase cascade. This study aimed to determine if a combination treatment augmented its apoptotic potential through other pathways except for the activation of the caspase cascade. Material and Methods : The NCI-H157 cells were treated with $As_2O_3$, sulindac and antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC). The cell viability was measured by a MTT assay, and the level of intracellular hydrogen peroxide ($H_2O_2$) generation was monitored fluorimetrically using a scopoletin-horse radish peroxidase (HRP) assay. Western blotting and mitochondrial membrane potential transition analysis were performed in order to define the mechanical basis of apoptosis. Results : The viability of the cells was decreased by a combination treatment of $As_2O_3$ and sulindac, and the cells were protected using antioxidants in a dose-dependent manner. The increased $H_2O_2$ generation by the combination treatment was inhibited by antioxidants. The combination treatment induced changes in the mitochondrial transmembrane potential as well as the expression of the Bcl-2 family proteins, and increased cytochrome c release into the cytosol. However, the antioxidants inhibited the effects of the combination treatment. Conclusion : Combination treatment with $As_2O_3$ and sulindac induces apoptosis in NCI-H157 human lung carcinoma cells via ROS generation with a mitochondrial dysfunction.

• Journal of the Korean Society of Food Science and Nutrition
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• v.41 no.8
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• pp.1100-1105
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• 2012

Green tea intake is known to have preventive effects against cancer. In this study, we evaluated the tumor suppressive effects of dietary green tea extracts (GTE) as a modulator on cisplatin in an established colon cancer mouse model. The cisplatin-induced cytotoxicity was determined with cell viability of the mouse colon cancer cell line (CT26) in vitro. The influence of GTE on the anti-tumor activity of cisplatin was evaluated by measuring tumor size with digital calipers in mice bearing CT26 colon carcinomas. The CT26 cell viability decreased to 93% at a $20{\mu}g/mL$ concentration of cisplatin. However, cell viability decreased to 15% with a combination of $20{\mu}g/mL$ cisplatin and GTE ($75{\mu}g/mL$). There were no apparent changes in cisplatin-induced cytotoxicity with GTE and epigallocathechin gallate (EGCG) treatments. Tumor size decreased in dietary GTE combining intra-peritoneal cisplatin-injected tumors bearing mice compared with cisplatin or GTE alone administered to tumor-bearing mice. These experiments showed that dietary GTE has a potentiating effect on the cisplatin anti-tumor activity of an established mice colon cancer model. Therefore, the GTE may be a candidate for modulators in anticancer treatments with cisplatin.