• Asian Pacific Journal of Cancer Prevention
• /
• 제15권6호
• /
• pp.2911-2916
• /
• 2014

Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromises its efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620) long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX). Compared with parental cell lines, $IC_{50}$s for various chemotherapeutic agents (oxaliplatin, cisplatin and doxorubicin) were increased in oxaliplatin-resistant cell lines and this was accompanied by activation of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1). Furthermore, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and $GST{\alpha}1/2$] expression and decreased reduced glutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell lines to chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeutic response.

• 생명과학회지
• /
• 제19권12호
• /
• pp.1705-1711
• /
• 2009

항암제 내성을 획득한 암세포는 많은 경우 다양한 세포 독성 물질에 대해 교차 내성을 나타낸다. 그러나 온열 치료가 내성 획득 종양에 적용 될 때의 종양 세포의 사멸 효과는 알려져 있지 않다. 본 연구는 시스플라틴에 내성을 갖는 위암 세포 주, SNU601/Cis2이 열충격에 반응하는 민감도와 세포 사멸 방식을 조사함으로써 약물 내성 종양의 온열 치료 효과를 예측하고자 하였다. 정상 위암 세포 주 SNU601/WT은 열충격에 매우 민감하게 반응하며 apoptosis로 사멸하지만, 내성 위암 세포 주 SNU601/Cis2는 미열충격에 내성을 나타내었으며 고열충격에 노출되자 necrosis로 사멸하였다. 또한 SNU601/Cis2에서 necrosis의 발생은 열충격에 의한 JNK1/2의 활성화와 HSP27의 발현저하 현상과 관련되어 있었다. Necrosis의 유도는 세포막 파괴에 의해 세포 내부 물질의 방출로 인한 주변 조직의 염증반응을 수반하는데, 이러한 염증 반응은 암의 성장을 촉진하고 암의 성상을 심화시키는 것으로 보고되고 있다. 이러한 관점에서, 온열 치료가 약물 치료와 병행 될 경우에는 교차 내성과 necrosis로 인한 역효과를 방지하기 위하여, 그 적용이 주의 깊게 이루어져야 할 것으로 판단된다.

• Biomolecules & Therapeutics
• /
• 제22권3호
• /
• pp.167-175
• /
• 2014

Chemotherapy has long been considered as one of useful strategies for cancer treatment. It is primarily based on the apoptosis that can selectively kill cancer cells. However, cancer cells can progressively develop an acquired resistance to apoptotic cell death, rendering refractory to chemo- and radiotherapies. Although the mechanism by which cells attained resistance to drug remains to be clarified, it might be caused by either pumping out of them or interfering with apoptotic signal cascades in response to cancer drugs. In case that cancer cells are defective in some part of apoptotic machinery by repeated exposure to anticancer drugs, alternative cell death mechanistically distinct from apoptosis could be adopted to remove cancer cells refractory to apoptosis-inducing agents. This review will mainly deal with harnessing of necrotic cell death, specifically, programmed necrosis and practical uses. Here, we begin with various defects of apoptotic death machinery in cancer cells, and then provide new perspective on programmed necrosis as an alternative anticancer approach.

• Biomolecules & Therapeutics
• /
• 제30권1호
• /
• pp.19-27
• /
• 2022

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

• Molecules and Cells
• /
• 제37권12호
• /
• pp.888-898
• /
• 2014

Pancreatic cancer is one of the most fatal cancers and is associated with limited diagnostic and therapeutic modalities. Currently, gemcitabine is the only effective drug and represents the preferred first-line treatment for chemotherapy. However, a high level of intrinsic or acquired resistance of pancreatic cancer to gemcitabine can contribute to the failure of gemcitabine treatment. To investigate the underlying molecular mechanisms for gemcitabine resistance in pancreatic cancer, we performed label-free quantification of protein expression in intrinsic gemcitabine-resistant and -sensitive human pancreatic adenocarcinoma cell lines using our improved proteomic strategy, combined with filter-aided sample preparation, single-shot liquid chromatography-mass spectrometry, enhanced spectral counting, and a statistical method based on a power law global error model. We identified 1931 proteins and quantified 787 differentially expressed proteins in the BxPC3, PANC-1, and HPDE cell lines. Bioinformatics analysis identified 15 epithelial to mesenchymal transition (EMT) markers and 13 EMT-related proteins that were closely associated with drug resistance were differentially expressed. Interestingly, 8 of these proteins were involved in glutathione and cysteine/methionine metabolism. These results suggest that proteins related to the EMT and glutathione metabolism play important roles in the development of intrinsic gemcitabine resistance by pancreatic cancer cell lines.

• 약학회지
• /
• 제52권1호
• /
• pp.67-72
• /
• 2008

The use of doxorubicin, which is one of the most effective anticancer agents, is often limited by occurrence of acquired resistance in tumor cells. GSH has been shown to be involved in the development of this drug resistance. Transcription factor Nrf2 governs the expression of GSH synthesizing glutamylcysteine ligase (GCL), as well as multiple phase 2 detoxifying enzymes. Here we show that Nrf2 is one of factors determining doxorubicin sensitivity. Nrf2-deficient fibroblasts (murine embryonic fibroblasts, MEF) were more susceptible to doxorubicin mediated cell death than wild-type cells. Doxorubicin treatment elevated levels of Nrf2-regulated genes including NAD(P)H: quinone oxidoreductase (Nqo1) and GCL in wild-type fibroblasts, while no induction was observed in Nrf2-deficient cells. Doxorubicin resistance in human ovarian SK-OV cells was reversed by treatment with L-buthionine-sulfoxamine (BSO), which is depleting intracellular GSH. Finally, transfection of SK-OV cells with Nrf2 siRNA resulted in exacerbated cytotoxicity following doxorubicin treatment compared to scrambled RNA control. These results indicate that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to anticancer agents.

• Tuberculosis and Respiratory Diseases
• /
• 제51권5호
• /
• pp.409-415
• /
• 2001

배 경 : 다제내성 폐결핵은 대부분은 획득내성에 의해 발생한다. 그러나 일부분에서 초회내성으로 발생하는데 이러한 환자들은 획득내성으로 인한 환자들과 차이가 있을 것으로 생각된다. 본 연구는 초회내성으로 진단된 다제내성 폐결핵 환자들의 임상적 특징을 조사하여 향후 이들에 대한 효과적인 치료에 지표로 삼고자 한다. 대상 및 방법 : 1995년 1월부터 1998년 12월까지 입원치료를 시행한 초회내성으로 진단된 다제내성 폐결핵 환자 30명을 대상으로 하였다. 임상적 특징을 조사하기 위하여 성별, 연령, 가족력, 균음전화 기간, 내성약제수, 치료약제와 흉부방사선상 NTA 분류를 이용한 병변의 정도 및 공동 유무와 치료기간 등을 조사하였다. 통계적 분석은 흉부방사선상 병변의 정도와 공동의 호전 여부를 윌콕슨 부호 순위 검정법을 이용하였고, Kaplan-Meier 방법으로 1년 및 4년 무병율을 조사하였다. 결 과 : 환자들의 평균나이는 평균 46.6세였고, 남녀비는 1:1이었다. 폐결핵 가족력이 있었던 경우는 6(20%)명이었다. 객담에서 균이 음전된 기간은 평균 2.6개월이었으며, 내성약제의 개수는 평균 7.6개였다. 환자들 중 23(67%)명에서 12개월 이하로 치료하였다. 그리고 초치료 처방으로 치료한 경우는 28(93%)명이었다. 흉부방사선상 병변의 정도와 공동은 치료 후 호전되었다(p<0.05). 총 13명의 환자들 평균 22.6개월간 외래 추적조사 결과 2(15%)명에서 재발을 관찰할 수 있었고, 1년 및 4년 무병율은 85%였다. 결 론 : 초회내성으로 진단된 다제내성 폐결핵의 경우에 있어서 초치료 처방으로 하여 흉부방사선상 병변의 정도와 공동의 호전 여부를 주의 깊게 관찰하면서 9-12개월을 치료한다면 성공적인 결과를 얻을 수 있을 것으로 생각된다.

• 한국동물위생학회지
• /
• 제43권1호
• /
• pp.31-37
• /
• 2020

Clostridial bacteria are zoonotic agents, which cause severe necrotizing enteritis, pseudo-membrane colitis, enterotoxemia to both humans and animals. The objective of this study was to monitor the antibiotic resistance of Clostridium isolates on clinical specimens from wild animals in Seoul zoo for 5 years. Clostridium isolates were verified by using Vitek2 compact machine. Antibiotic susceptibility was assessed by antibiotic disc diffusion test, which was followed by Kirby-Bauer disc diffusion test method. The frequency of Antimicrobial resistance of Clostridium isolate was the greatest in gentamicin (87%), then in order of amikacin (80%). There were 55.6% of Clostridium isolates showed multiple drug resistance (MDR). These results showed that a lot of Clostridial bacteria from wild animals in Seoul zoo were acquired antibiotic resistance. Because of the wild animal's aggressive manner, it has been hard to collect clinical samples from wild animals in a zoo to exam antibiotic susceptibility. For these reasons, empirical use of antibiotics has been performed in frequently. It may cause to increase the emergence of antibiotic resistance bacteria. In addition, the antibiotic resistance bacteria from zoo animals can be spread to other wild animals which inhabit around the zoo. Therefore, regular monitoring of antibiotic resistance Clostridial bacteria is important to protect animals and humans from Clostridial diseases.

• Childhood Kidney Diseases
• /
• 제17권1호
• /
• pp.19-24
• /
• 2013

목적: 장구균은 원내 감염의 중요한 세균으로 최근 그 빈도가 많아지며, 항생제 내성을 갖는 경우도 증가하면서 활발한 연구가 이루어지고 있다. 하지만 소아의 지역사회 획득 요로감염의 원인으로서 장구균에 대한 연구는 소수에 불과하여 이에 저자들은 부산 경남 지역에서 발생하는 장구균에 의한 지역사회 획득 요로감염의 임상적 특징과 항생제 감수성 등을 조사하고자 하였다. 방법: 20010년 1월부터 2013년 1월까지 첫 번째 요로감염으로 부산대학교 어린이병원에 입원 하였던 18세 미만의 환자 중 장구균과 대장균이 배양된 환자를 대상으로 하여 의무 기록을 후향적으로 분석하였다. 의무 기록을 통해 환자의 성별, 진단 시 연령, 기저 신 질환, 최근 항생제 복용력, 영상 검사의 결과, 세균의 항생제 감수성, 처음 사용한 항생제에 대한 반응 유무 등을 조사하였다. 결과: 2010년 1월부터 2013년 1월까지 첫 번째 요로감염이 확인되어 치료한 환자는 201명으로 이 중 대장균은 154명(76.6%)에서 분리되었고, 장구균은 11명(5.5%)에서 분리되었으며 배양된 장구균은 모두 Enterococcus feacalis였다. 장구균이 배양된 집단에서 배뇨방광요도조영술 검사를 시행한 7명 중 4명(57.1%)에서 방광요관역류가 발견되었고, 이들 모두 DMSA 신스캔에서 신 반흔을 보였으며 현재까지 3명의 환자가 방광요관역류에 대한 비뇨기과적 교정 시술을 시행 받았다. 대장균이 배양된 집단에서는 121명의 환자에서 배뇨방광요도조영술 검사가 시행되어 23명이 방광요관역류로 진단되었고, 현재까지 11명이 비뇨기과적 교정술을 시행 받았다. 대장균에 의한 요로감염 환자들과 비교하였을 때 장구균 요로감염 환자에서 방광요관역류와 수술적 교정술의 빈도가 통계학적으로 의미 있게 높았다. 분리된 장구균의 항생제 감수성 검사에서 ampicillin, vancomycin, linezolid에 대해서는 100% 감수성을 보였으며 tetracycline에 대해서는 100% 내성을 보였고 Trimethoprim/sulfamethoxazole에는 71.4%, quinolone계열인 ciprofloxacin에는 20% 내성을 나타냈다. 결론: 부산 경남 지역의 지역사회 획득 장구균 요로감염은 흔하지 않지만, 근본적인 요로계의 이상을 동반할 가능성이 높으므로 환자에 대한 영상학적 평가가 이루어져야 할 것으로 생각된다.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권3호
• /
• pp.1391-1396
• /
• 2014

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is used for its treatment; however, drug resistance is a major obstacle. Expression of Met has been associated with both primary and acquired resistance to gefitinib, but the mechanisms regulating its expression are not fully understood. Recently, miRNAs such as miR-130a have been shown to play a role in gefitinib resistance, but importance in NSCLC and relationships with Met have not been fully explored. Here we show that miR-130a is over-expressed in gefitinibsensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Moreover, miR-130a expression was negatively correlated with that of Met. Further analysis revealed that over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines, suggesting that miR-130a overcomes gefitinib resistance. We also demonstrated that miR-130a binds to the 3'-UTR of Met and significantly suppresses its expression. Finally, our results showed that over-expressing Met could "rescue" the functions of miR-130a regarding cell apoptosis and proliferation after cells are treated with gefitinib. These findings indicate that the miR-130a/Met axis plays an important role in gefitinib resistance in NSCLC. Thus, the miR-130a/Met axis may be an effective therapeutic target in gefitinib-resistant lung cancer patients.