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Ferrer RE, Ong MC, Jacinto S. Extract of Codiaeum luzonicum Merr. overcomes multidrug resistance in human colon cancer cells by modulating P-glycoprotein. Asian Pac J Trop Biomed 2022. [DOI: 10.4103/2221-1691.354431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Yakout ESMA, Salam HAAE, Nawwar GAM. Bioactive Small Molecules Having a Fatty Residue. Part VI: Synthesis, Cytotoxicity Evaluation, and Molecular Docking Studies of New Pyrimidine Derivatives as Antitumor Agents. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY 2021. [DOI: 10.1134/s107042802012026x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Syed SB, Lin SY, Arya H, Fu IH, Yeh TK, Charles MRC, Periyasamy L, Hsieh HP, Coumar MS. Overcoming vincristine resistance in cancer: Computational design and discovery of piperine-inspired P-glycoprotein inhibitors. Chem Biol Drug Des 2020; 97:51-66. [PMID: 32633857 DOI: 10.1111/cbdd.13758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/05/2020] [Accepted: 06/28/2020] [Indexed: 01/03/2023]
Abstract
P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB ChR 8-5, SW480-VCR, and HCT-15). Both the analogs significantly increased the vincristine efficacy in MDR cancer cell lines at low micromole concentrations. Specifically, 3 caused complete reversal of vincristine resistance in KB ChR 8-5 cells and found to act as competitive inhibitor of P-gp as well as potentiated the vincristine-induced NF-KB-mediated apoptosis. Therefore, 3 ((2E,4E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dien-1-one) can serve as a potential P-gp inhibitor for in vivo investigations, to reverse multidrug resistance in cancer.
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Affiliation(s)
- Safiulla Basha Syed
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, India.,DBT-Interdisciplinary Program in Life Sciences, Pondicherry University, Kalapet, India
| | - Shu-Yu Lin
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Hemant Arya
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, India
| | - I-Hsuan Fu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | - Teng-Kuang Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
| | | | - Latha Periyasamy
- Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Kalapet, India
| | - Hsing-Pang Hsieh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.,Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
| | - Mohane Selvaraj Coumar
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, India
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Shanmugam T, Joshi N, Ahamad N, Deshmukh A, Banerjee R. Enhanced absorption, and efficacy of oral self-assembled paclitaxel nanocochleates in multi-drug resistant colon cancer. Int J Pharm 2020; 586:119482. [PMID: 32492505 DOI: 10.1016/j.ijpharm.2020.119482] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 05/15/2020] [Accepted: 05/25/2020] [Indexed: 11/18/2022]
Abstract
Chemotherapy in drug-resistant cancers remains a challenge. Owing to associated poor bioavailability, oral administration of hydrophobic anticancer drugs like paclitaxel has been quite challenging, with the scenario being further complicated by Pgp efflux in drug-resistant tumours. We developed a novel nanocochleates (CPT) system encapsulating paclitaxel (PTX) to treat resistant colon cancer by oral administration. PTX encapsulated nanocochleates (PTX-CPT), made up of phosphatidylserine in size range of 350-600 nm with -20 ± 5.2 mV zeta potential were protected from degradation at acidic gastric pH and showed sustained PTX release over 48 h under intestinal pH condition. In vitro cytotoxicity studies on HCT-116 & HCT-15 cells (multi-drug resistant) established IC50 value of <10 and 69 nM, respectively, which was significantly lower when compared to commercial Taxol formulation. Further, the in vivo efficacy with five oral doses of 30 mg/kg PTX-CPT in an HCT-15 drug-resistant colon cancer xenograft mouse model showed more than 25 fold reduction in the tumour growth inhibition as compared to intravenous Taxol which showed just 1.94% inhibition. Interestingly, PTX-CPT treated mice also showed significantly lower proliferation index and microvessel density when compared to Taxol treated mice. Nanocochleates showed lower toxicity with at LD-50 value greater than 300 mg/kg as described in OECD 423 guideline. The enhanced efficacy of PTX-CPT speculated due to its internalization by active endocytosis, ability to escape Pgp efflux, and due to a combined effect of the pro-apoptotic and antiangiogenic role. Taken together, the results suggested the PTX-CPT a promising strategy for efficiently treating drug-resistant colon cancer orally.
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Affiliation(s)
- Thanigaivel Shanmugam
- Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai 400076, India
| | - Nitin Joshi
- Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai 400076, India
| | - Nadim Ahamad
- Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai 400076, India
| | - Atul Deshmukh
- Oral & Maxillofacial Pathology & Immunohistochemistry Centre, Mumbai 400003, India
| | - Rinti Banerjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai 400076, India.
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Dante RAS, Ferrer RJE, Jacinto SD. Leaf Extracts from Dillenia philippinensis Rolfe Exhibit Cytotoxic Activity to both Drug-Sensitive and Multidrug-Resistant Cancer Cells. Asian Pac J Cancer Prev 2019; 20:3285-3290. [PMID: 31759350 PMCID: PMC7063009 DOI: 10.31557/apjcp.2019.20.11.3285] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Indexed: 01/10/2023] Open
Abstract
Background: Cancer is one of the leading causes of illness and death worldwide. Only palliative therapeutic options are available for many types of cancers, and most anticancer drugs in clinical use exhibit significant side effects. It is therefore important to develop new anticancer drugs that are more effective and less toxic. In this study, we evaluate the bioactivity of a Philippine endemic plant, “katmon” or Dillenia philippinensis, and its potential use in cancer therapy. Methods: The cytotoxicity of the crude leaf extract, partitions, and isocratic column chromatography fractions of Dillenia philippinensis was determined in vitro by MTT assay against drug-sensitive cancer cell lines MCF7 (human breast adenocarcinoma) and HCT 116 (human colorectal carcinoma), as well as against moderately multidrug resistant (MDR) cancer cell line HCT-15 (human colorectal carcinoma) and its highly MDR subline HCT-15/Dox. The selectivity of the extract to cancer cells was determined by computing for the selectivity index (SI) with respect to normal mouse embryonic fibroblasts (NIH/3T3) cell line. To check for a possible mechanism for overcoming cancer multiple drug resistance, Calcein-AM assay was performed to assess the activity of the extract against P-glycoprotein-activated efflux pump. Results: Dillenia philippinensis (DP1) fraction from the hexane partition exhibited cytotoxicity (IC50< 30 µg/ml) against MCF7, HCT 116, HCT-15, and HCT-15/Dox cells. DP1 also exhibited a moderate level of selectivity against cancer cells over normal cells as supported by the SI computed from the IC50 value obtained for the normal cell line. DP1 was able to inhibit P-glycoprotein (P-gp) activity in a dose-dependent manner, suggesting its possible role in targeting cancer cells with overexpressed P-gp. Conclusion: The present findings thus demonstrate the potential chemotherapeutic properties of D. philippinensis which can be promising for future drug development against cancer.
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Affiliation(s)
- Rachelle Anne S Dante
- Institute of Biology, University of the Philippines, Diliman, Quezon City, Philippines
| | - Regina Joyce E Ferrer
- Institute of Biology, University of the Philippines, Diliman, Quezon City, Philippines
| | - Sonia D Jacinto
- Institute of Biology, University of the Philippines, Diliman, Quezon City, Philippines
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Park JS, Jeong S, Lee DH, Maeng JH, Park IS, Park S. Antitumor effect of the paclitaxel-eluting membrane in a mouse model. Oncol Lett 2018; 16:4537-4542. [PMID: 30214588 DOI: 10.3892/ol.2018.9164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 09/01/2017] [Indexed: 12/31/2022] Open
Abstract
Local treatment of primary bile duct cancer, which grows locally at the primary lesion and seldom metastasizes to distant sites, is challenging. The present study evaluated the antitumor effect, systemic toxicity, biodistribution and survival benefit of the paclitaxel-eluting polyurethane membrane in a tumor model. Membranes containing various amounts of paclitaxel (0, 100, 300, 600 and 1,200 µg/disc) were inserted beneath the tumor mass in mouse models. Tumor size and body weight of the tumor models were monitored for 26 days after insertion of the membrane. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was performed in the tumor tissues. High-performance liquid chromatography was performed for evaluation of paclitaxel concentration in peripheral tissues. Tumor volumes on day 26 of membrane treatment were decreased in a dose-dependent manner. No significant difference in body weight was observed in the groups. A greater number of apoptotic cells were counted per high power field in tumor tissues following an increase of paclitaxel concentration. In the 1,200 µg-group, concentrations of paclitaxel were significantly higher in tumors compared with those of other tissues and serum. The paclitaxel-eluting membrane demonstrated a significant and dose-dependent antitumor activity, and did not exert systemic toxicity in the tumor model.
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Affiliation(s)
- Jin-Seok Park
- Department of Internal Medicine, Inha University School of Medicine, Incheon 400-711, Republic of Korea
| | - Seok Jeong
- Department of Internal Medicine, Inha University School of Medicine, Incheon 400-711, Republic of Korea
| | - Don Haeng Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon 400-711, Republic of Korea
| | - Jin Hee Maeng
- Utah-Inha DDS and Advanced Therapeutics Research Center, Incheon 461-713, Republic of Korea
| | - In Suh Park
- Department of Pathology, Inha University School of Medicine, Incheon 400-711, Republic of Korea
| | - Sangsoo Park
- Department of Biomedical Engineering, Eulji University, Seongnam, Gyeonggi 461-713, Republic of Korea
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Generation and characterization of a paclitaxel-resistant human gastric carcinoma cell line. Anticancer Drugs 2018; 29:491-502. [DOI: 10.1097/cad.0000000000000601] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Computer-aided design, synthesis, and biological studies of anticological nitrogen-containing tetraphosphonic acids against melanoma. MONATSHEFTE FUR CHEMIE 2018. [DOI: 10.1007/s00706-018-2196-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Cyclodextrin–PEG conjugate-wrapped magnetic ferrite nanoparticles for enhanced drug loading and release. APPLIED NANOSCIENCE 2018. [DOI: 10.1007/s13204-018-0798-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Abstract
Magnetic nanoparticles are envisaged to overcome the impediments in the methods of targeted drug delivery and hence cure cancer effectively. We report herein, manganese ferrite nanoparticles, coated with β-cyclodextrin-modified polyethylene glycol as a carrier for the drug, camptothecin. The particles are of the size of ~ 100 nm and they show superparamagnetic behaviour. The saturation magnetization does not get diminished on polymer coverage of the nanoparticles. The β-cyclodextrin–polyethylene glycol conjugates are characterized using NMR and mass spectrometric techniques. By coating the magnetic nanoparticles with the cyclodextrin–tethered polymer, the drug-loading capacity is enhanced and the observed release of the drug is slow and sustained. The cell viability of HEK293 and HCT15 cells is evaluated and the cytotoxicity is enhanced when the drug is loaded in the polymer-coated magnetic nanoparticles. The noncovalent-binding based and enhanced drug loading on the nanoparticles and the sustained release make the nanocarrier a promising agent for carrying the payload to the target.
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Wang C, Guo L, Wang S, Wang J, Li Y, Dou Y, Wang R, Shi H, Ke Y, Liu H. Anti-proliferative effect of Jesridonin on paclitaxel-resistant EC109 human esophageal carcinoma cells. Int J Mol Med 2017; 39:645-653. [PMID: 28204832 PMCID: PMC5360389 DOI: 10.3892/ijmm.2017.2867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/13/2017] [Indexed: 12/19/2022] Open
Abstract
Chemoresistance to anticancer drugs is a major obstacle in the efforts to develop a successful treatment strategy for esophageal squamous carcinoma (ESCC). Thus, the exploration of new drugs and treatment strategies for combating resistance are of utmost importance. In this study, we investigated the antitumor drug resistance activity of Jesridonin, a new ent-kaurene diterpenoid, and its possible mechanisms of action using the resistant cancer cell line, EC109/Taxol. MTT assay revealed that Jesridonin had similar IC50 values against EC109 paclitaxel-sensitive cells and drug-resistant EC109/Taxol cells in vitro. In mice, Jesridonin effectively prevented the growth of EC109/Taxol tumor xenografts without exerting any significant toxicity. In addition, Jesridonin significantly inhibited the proliferation of EC109/Taxol cells, induced apoptosis and arrested the cell cycle at the G2/M phase. Furthermore, western blot analysis revealed that Jesridonin upregulated the expression of p53, p53 upregulated modulator of apoptosis (PUMA), cleaved-caspase-9 and cleaved-caspase-3 in EC109/Taxol cells, and downregulated the expression of procaspase-3, procaspase-9 and Bcl-2 in the EC109/Taxol cells in a concentration-dependent manner. Overall, our results demonstrate that Jesridonin may have potential for use in the treatment of paclitaxel-resistant ESCC. The data of the present study may lead to the development of novel treatment strategies for paclitaxel-resistant tumors.
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Affiliation(s)
- Cong Wang
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Liubin Guo
- Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China
| | - Saiqi Wang
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Junwei Wang
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Yongmei Li
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Yinhui Dou
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Ran Wang
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Hongge Shi
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Yu Ke
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
| | - Hongmin Liu
- Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou, Henan 450001, P.R. China
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XU MINGJIE, JIANG DONGHAI, SHEN JIAYING, ZHENG HUILIN, FAN WEIMIN. Distinct characterization of two vinorelbine-resistant breast cancer cell lines developed by different strategies. Oncol Rep 2016; 35:2355-63. [DOI: 10.3892/or.2016.4566] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 12/17/2015] [Indexed: 11/05/2022] Open
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Xiao M, Wang J, Lin Z, Lu Y, Li Z, White SW, Miller DD, Li W. Design, Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties. PLoS One 2015; 10:e0129807. [PMID: 26070194 PMCID: PMC4466525 DOI: 10.1371/journal.pone.0129807] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 05/13/2015] [Indexed: 02/05/2023] Open
Abstract
The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC50 values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 μM for UC-112 vs. 0.5 μM for 4g, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents.
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Affiliation(s)
- Min Xiao
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Jin Wang
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Zongtao Lin
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Yan Lu
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Zhenmei Li
- Department of Structure Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
| | - Stephen W. White
- Department of Structure Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
| | - Duane D. Miller
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Wei Li
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- * E-mail:
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Wang C, Zhang W, Fu M, Yang A, Huang H, Xie J. Establishment of human pancreatic cancer gemcitabine‑resistant cell line with ribonucleotide reductase overexpression. Oncol Rep 2014; 33:383-90. [PMID: 25394408 DOI: 10.3892/or.2014.3599] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 08/29/2014] [Indexed: 12/12/2022] Open
Abstract
A gemcitabine (GEM)-resistant human pancreatic cancer cell line (PANC-1RG7) was established in vitro by gradually increasing GEM concentrations and cloning cell cultures to develop a cellular model of acquired drug resistance studies. We found that PANC-1RG7 cells exhibited significantly different morphological characteristics from parental cells. PANC-1RG7 cells grew slowly (p<0.05), yet the cell cycle remained unchanged (p>0.05). PANC-1RG7, with a resistance index to GEM of 39.9, showed cross-resistance characteristics to methotrexate, gefitinib, cisplatin and 5-fluorouracil. The proliferation inhibition of GEM was significantly reduced in vivo (p<0.05). The known resistance-associated genes and proteins we detected remained unchanged, with the exception of cytidine deaminase, multidrug resistance-related protein and breast cancer resistance protein genes, which decreased; by contrast, 5'-nucleotidase, ribonucleotide reductase (RRM) 1 and RRM2 proteins increased (p<0.05). Therefore, a cell line with acquired GEM resistance was established successfully. Resistance was acquired by overexpressing RRM1 and RRM2 proteins.
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Affiliation(s)
- Congfei Wang
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Weiwei Zhang
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian 350004, P.R. China
| | - Mingjuan Fu
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian 350004, P.R. China
| | - Aiqin Yang
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian 350004, P.R. China
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Jieming Xie
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian 350004, P.R. China
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WANG CONG, GUO LIUBIN, MA JUNYUAN, LI YONGMEI, LIU HONGMIN. Establishment and characterization of a paclitaxel-resistant human esophageal carcinoma cell line. Int J Oncol 2013; 43:1607-17. [DOI: 10.3892/ijo.2013.2083] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 08/05/2013] [Indexed: 11/05/2022] Open
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Rocha-Lima CM, Bayraktar S, Macintyre J, Raez L, Flores AM, Ferrell A, Rubin EH, Poplin EA, Tan AR, Lucarelli A, Zojwalla N. A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors. Cancer 2012; 118:4262-70. [PMID: 22294459 DOI: 10.1002/cncr.27428] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 12/19/2011] [Accepted: 12/09/2011] [Indexed: 01/04/2023]
Abstract
BACKGROUND E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids). METHODS In a phase 1 study, E7974 was given intravenously over a 2- to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT). RESULTS Twenty-eight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m(2) , 0.27 mg/m(2) , 0.36 mg/m(2) , 0.45 mg/m(2) , and 0.56 mg/m(2) ) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m(2) , where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours). CONCLUSIONS This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m(2).
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Affiliation(s)
- Caio M Rocha-Lima
- Department of Medical Oncology, University of Miami and Sylvester Comprehensive Cancer Center, Miami, Florida, USA.
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Abu-Zaied MA, El-Telbani EM, Elgemeie GH, Nawwar GAM. Synthesis and in vitro anti-tumor activity of new oxadiazole thioglycosides. Eur J Med Chem 2010; 46:229-35. [PMID: 21115211 DOI: 10.1016/j.ejmech.2010.11.008] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 11/03/2010] [Accepted: 11/05/2010] [Indexed: 01/02/2023]
Abstract
A facile, convenient and high yielding synthesis of novel thioglycosides incorporating 1,3,4-oxadiazole, triazole and or triazine moieties from readily available starting materials has been described. The key step of this protocol is the formation of 3-isobutyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3) via condensation between methyl iso-butyl ketone and phenylhydrazine followed by application of Vilsmeier-Haack reaction. 3 was converted either to 1,3,4-oxadiazole derivative or condensed with O-aminothiols to give the bases 8, 19 and 20 in good yields, respectively. The aglycons 8, 19, and 20 were coupled with different activated halosugars in the presence of basic medium. Pharmacological evaluation of compounds 8, 14, 16 and 22 in vitro against 2-cell lines MCF-7 (breast) and HEPG2 (liver) revealed them to possess high anti-tumor activities with IC(50) values ranging from 2.67-20.25 (μg/mL) for breast cell line (MCF-7) and 4.62-43.6 (μg/mL) for liver cell line (HEPG2). None of the tested compounds exhibited any toxicity in doses up to 500 mg kg(-1) of the animal body weight.
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Affiliation(s)
- M A Abu-Zaied
- National Research Centre, Green Chemistry Department, 12622 Dokki, Cairo, Egypt
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Argov M, Bod T, Batra S, Margalit R. Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization. Eur J Pharm Sci 2010; 41:53-9. [PMID: 20553861 DOI: 10.1016/j.ejps.2010.05.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 05/17/2010] [Accepted: 05/19/2010] [Indexed: 10/19/2022]
Abstract
P-glycoprotein (Pgp) is a major ABC transporter responsible for multidrug-resistance (MDR) in cancer chemotherapy. Pre-clinical MDR modulation studies identified promising chemosensitizers, but none are in the clinic yet. Two novel progesterone-derived carbamates (11-carbamic acid N,N-dibenzyl progesterone ester and 11-carbamic acid N,N-dibutyl progesterone ester) were examined as potential chemosensitizers in the Pgp-expressing human colon cancer line HCT-15, applying the classical MDR-drugs paclitaxel and doxorubicin. The major findings were: (1) Pgp was expressed in the HCT-15 cells in both the cell and the nuclear membranes, (2) at the low dose range of 1-5 microM, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4h) for doxorubicin and 300% (18h) for paclitaxel, (iii) reduced drug efflux from the cell, 2-fold and 4-fold for doxorubicin and for paclitaxel, respectively. Based on detailed kinetic analysis, using liposomes to model paclitaxel diffusion through cell membranes, efflux slowdown can be attributed to reduction in the rate constant of drug diffusion through Pgp, and not to Pgp blockage. Chemosensitization was consistently-better for paclitaxel (cytosol-operating) than for doxorubicin (nuclear-operating) implying linkage between P-glycoprotein localization and loci of drug action. Mapping intracellular locations of MDR-pumps may assist therapeutic strategies.
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Affiliation(s)
- Mirit Argov
- Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel
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18
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Purine analogs sensitize the multidrug resistant cell line (NCI-H460/R) to doxorubicin and stimulate the cell growth inhibitory effect of verapamil. Invest New Drugs 2009; 28:482-92. [PMID: 19533022 DOI: 10.1007/s10637-009-9277-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Accepted: 05/25/2009] [Indexed: 10/20/2022]
Abstract
The resistant cell line NCI-H460/R and its counterpart NCI-H460 were used to investigate the ability of purine analogs to overcome multidrug resistance (MDR) that seriously limit the efficacy of lung cancer regimens with chemotherapeutic agents. Two purine analogs, sulfinosine (SF) and 8-Cl-cAMP, exerted dose-dependent effects on cell growth in both parental and resistant cell lines. They significantly decreased mdr1 expression in NCI-H460/R cells. Low concentrations (1 microM) of SF and 8-Cl-cAMP in combination with doxorubicin (DOX) exerted synergistic growth inhibition in both cell lines. Pretreatment with SF and 8-Cl-cAMP improved the sensitivity to DOX more than verapamil (VER), the standard modulator of MDR. The increased accumulation of DOX observed after the treatment with SF and 8-Cl-cAMP was consistent with the results obtained with VER. VER stimulated the effect of 8-Cl-cAMP on DOX cytotoxicity and mdr1 expression. Combinations of either SF or 8-Cl-cAMP with VER at clinically acceptable concentrations exhibited synergistic effects on cell growth inhibition in the resistant cell line. SF and 8-Cl-cAMP modulated MDR in NCI-H460/R cells, especially when applied before DOX administration. This feature, together with their ability to reverse MDR, renders the purine analogs (in combination with VER) as potential candidates for improving the clinical activity of existing lung cancer therapeutics.
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Kuwahara Y, Li L, Baba T, Nakagawa H, Shimura T, Yamamoto Y, Ohkubo Y, Fukumoto M. Clinically relevant radioresistant cells efficiently repair DNA double-strand breaks induced by X-rays. Cancer Sci 2009; 100:747-52. [PMID: 19215227 PMCID: PMC11158180 DOI: 10.1111/j.1349-7006.2009.01082.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Radiotherapy is one of the major therapeutic modalities for eradicating malignant tumors. However, the existence of radioresistant cells remains one of the most critical obstacles in radiotherapy and radiochemotherapy. Standard radiotherapy for tumor treatment consists of approximately 2 Gy once a day, 5 days a week, over a period of 5-8 weeks. To understand the characteristics of radioresistant cells and to develop more effective radiotherapy, we established a novel radioresistant cell line, HepG2-8960-R with clinical relevance from parental HepG2 cells by long-term fractionated exposure to 2 Gy of X-rays. HepG2-8960-R cells continued to proliferate with daily exposure to 2 Gy X-rays for more than 30 days, while all parental HepG2 cells ceased. After exposure to fractionated 2 Gy X-rays, induction frequencies of micronuclei and remaining foci of gamma-H2AX in HepG2-8960-R were less than those in HepG2. Flow cytometric analysis revealed that the proportion of cells in S- and G2/M-phase of the cell cycle was higher in HepG2-8960-R than in HepG2. These suggest that the response of clinically relevant radioresistant (CRR) cells to fractionated radiation is not merely an accumulated response to each fractionated radiation. This is the first report on the establishment of a CRR cell line from an isogenic parental cell line.
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Affiliation(s)
- Yoshikazu Kuwahara
- Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
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20
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Argov M, Kashi R, Peer D, Margalit R. Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. Cancer Lett 2008; 274:118-25. [PMID: 18851896 DOI: 10.1016/j.canlet.2008.09.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2008] [Revised: 07/21/2008] [Accepted: 09/03/2008] [Indexed: 12/14/2022]
Abstract
Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it's modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin's cytotoxicity (10-fold), increased doxorubicin's intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%). In vivo, mild treatment with a doxorubicin-fluoxetine combination slowed-down tumor progression significantly (p<0.001 vs. doxorubicin alone), comparable to aggressive treatment with bevacizumab. Collectively, our results suggest that combinations of fluoxetine with chemotherapeutic drugs (P-glycoprotein substrates) are worthy of further pursuit for moderate MDR in the clinic.
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Affiliation(s)
- Mirit Argov
- Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel
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21
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Martineti V, Silvestri S, Tonelli F, Brandi ML. Control of colon cancer development and progression by selected estrogen receptor modulators. Expert Rev Endocrinol Metab 2008; 3:503-511. [PMID: 30290437 DOI: 10.1586/17446651.3.4.503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Estrogens behave as protective agents on the development of colorectal cancer, and hormonal-replacement therapy is associated with an increased survival rate in women with this disease, indicating that estrogenic therapy correlates with a better prognosis. The protective effect of estrogens on Fcolorectal cancer development and progression is presumably related to the expression of estrogen receptors in colon mucosa, with the estrogen receptor-β isoform being the predominant one. This observation suggests that estrogen receptor-β could have an inhibitory effect on colorectal cancer cell proliferation and a regulatory effect on colonic mucosa cell growth, opening the discussion on a pharmacologic approach to colorectal cancer prevention and therapy based on estrogenic compounds.
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Affiliation(s)
- Valentina Martineti
- a Department of Internal Medicine, School of Medicine, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
| | - Sandra Silvestri
- b Specialist in Endocrinology and Metabolic Disease, Expert Clinical Research Physician, Internal Medicine, Eli Lilly Italia S.p.A., Via Gramsci 731, 50019 Sesto Fiorentino, FI, Italy.
| | - Francesco Tonelli
- c Department of Clinical Physiopathology, School of Medicine - University of Florence, Viale Morgagni 85, 50134 Firenze, Italy.
| | - Maria Luisa Brandi
- d Department of Internal Medicine, School of Medicine - University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
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Abstract
Chemotherapy resistance is one of the most prevalent obstacles to the treatment of cancer, resulting in increased mortality and prolonged exposure to cytotoxic agents with no treatment benefit. One of the tools utilized in the study of mechanisms of chemotherapy resistance are established cell lines derived from human neoplasms. These cell lines can be challenged in vitro with controlled chemotherapy doses to produce chemotherapy-resistant variants. Analysis of these novel chemotherapy-resistant cell lines may then identify genetic and proteomic changes which are associated with the resistant phenotype. Two very important mediators of chemotherapy resistance (P-glycoprotein and multidrug resistance protein-1) were initially identified in chemotherapy-resistant cell lines. To make these in-vitro studies clinically relevant it is, however, necessary to duplicate as far as possible the treatment conditions used in vivo. Considerations should include clinically relevant drug concentrations, such as those derived from peak plasma values, and the type of treatment schedule to be employed.
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Affiliation(s)
- Mark B Watson
- Cancer Biology Proteomics Group, Postgraduate Medical Institute of the University of Hull, Hull, UK
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Zhai BJ, Shao ZY, Zhao CL, Hu K, Wu F. Development and characterization of multidrug resistant human hepatocarcinoma cell line in nude mice. World J Gastroenterol 2006; 12:6614-9. [PMID: 17075973 PMCID: PMC4125665 DOI: 10.3748/wjg.v12.i41.6614] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a multidrug resistant (MDR) cell sub-line from the human hepatocarcinoma cell line (HepG2) in nude mice.
METHODS: HepG2 cell cultures were incubated with increasing concentrations of adriamycin (ADM) to develop an ADM-resistant cell subline (HepG2/ADM) with cross-resistance to other chemotherapeutic agents. Twenty male athymic BALB/c-nu/nu mice were randomized into HepG2/nude and HepG2/ADM/nude groups (10 in each group). A cell suspension (either HepG2 or HepG2/ADM) was injected subcutaneously into mice in each group. Tumor growth was recorded, and animals were sacrificed 4-5 wk after cell implantation. Tumors were prepared for histology, and viable tumor was dispersed into a single-cell suspension. The IC50 values for a number of chemotherapeutic agents were determined by 2, 3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (MTT) assay. Rhodamine-123 retention/efflux and the level of resistance-associated proteins were determined by flow cytometry. The mRNA expression of mdr1, mrp and lrp genes was detected using reverse transcriptase polymerase chain reaction (RT-PCR) in HepG2/nude and HepG2/ADM/nude groups.
RESULTS: The appearances of HepG2/nude cells were slightly different from those of HepG2/ADM/nude cells. Similar tumor growth curves were determined in both groups. A cross-resistance to ADM, vincristine, cisplatin and 5-fluorouracil was seen in HepG2/ADM/nude group. The levels of P-glycoprotein and multidrug resistance-associated proteins were significantly increased. The mRNA expression levels of mdr1, mrp and lrp were higher in HepG2/ADM/nude cells.
CONCLUSION: ADM-resistant HepG2 subline in nude mice has a cross resistance to chemotherapeutic drugs. It may be used as an in vivo model to investigate the mechanisms of MDR, and explore the targeted approaches to overcoming MDR.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Animals
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Proliferation
- Drug Resistance, Multiple/genetics
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Mice
- Mice, Nude
- Multidrug Resistance-Associated Proteins/genetics
- Multidrug Resistance-Associated Proteins/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rhodamine 123
- Vault Ribonucleoprotein Particles/genetics
- Vault Ribonucleoprotein Particles/metabolism
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Affiliation(s)
- Bao-Jin Zhai
- Clinical Center for Tumor Therapy of 2nd Affiliated Hospital, Box 153, Institute of Ultra-sonic Engineering in Medicine, Chongqing University of Medical Sciences, 1 Medical College Road, Chongqing 400016, China
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24
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Smith L, Watson MB, O'Kane SL, Drew PJ, Lind MJ, Cawkwell L. The analysis of doxorubicin resistance in human breast cancer cells using antibody microarrays. Mol Cancer Ther 2006; 5:2115-20. [PMID: 16928833 DOI: 10.1158/1535-7163.mct-06-0190] [Citation(s) in RCA: 168] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Doxorubicin is considered to be the most effective agent in the treatment of breast cancer patients. Unfortunately, resistance to this agent is common, representing a major obstacle to successful treatment. The identification of novel biomarkers that are able to predict treatment response may allow therapy to be tailored to individual patients. Antibody microarrays provide a powerful new technique, enabling the global comparative analysis of many proteins simultaneously. This technology may identify a panel of proteins to discriminate between drug-resistant and drug-sensitive samples. The Panorama Cell Signaling Antibody Microarray was exploited to analyze the MDA-MB-231 breast cancer cell line and a novel derivative, which displays significant resistance to doxorubicin at clinically relevant concentrations. The microarray comprised 224 antibodies selected from a variety of pathways, including apoptotic and cell signaling pathways. A standard >/=2.0-fold cutoff value was used to determine differentially expressed proteins. A decrease in the expression of mitogen-activated protein kinase-activated monophosphotyrosine (phosphorylated extracellular signal-regulated kinase; 2.8-fold decrease), cyclin D2 (2.5-fold decrease), cytokeratin 18 (2.5-fold decrease), cyclin B1 (2.4-fold decrease), and heterogeneous nuclear ribonucleoprotein m3-m4 (2.0-fold decrease) was associated with doxorubicin resistance. Western blotting was exploited to confirm results from the antibody microarray experiment. These results suggest that antibody microarrays can be used to identify novel biomarkers and further validation may reveal mechanisms of chemotherapy resistance and identify potential therapeutic targets. [Mol Cancer Ther 2006;5(8):2115-20].
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Affiliation(s)
- Laura Smith
- Cancer Biology Proteomics Group, Postgraduate Medical Institute of the University of Hill in association with the Hull-York Medical School, University of Hull, Hull, United Kingdom
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25
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Zhang LH, Wu L, Raymon HK, Chen RS, Corral L, Shirley MA, Narla RK, Gamez J, Muller GW, Stirling DI, Bartlett JB, Schafer PH, Payvandi F. The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity. Cancer Res 2006; 66:951-9. [PMID: 16424030 DOI: 10.1158/0008-5472.can-05-2083] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
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Affiliation(s)
- Ling-Hua Zhang
- Division of Immunotherapeutics, Celgene Corp., 86 Morris Avenue, Summit, NJ 07901, USA.
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26
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Tepsiri N, Chaturat L, Sripa B, Namwat W, Wongkham S, Bhudhisawasdi V, Tassaneeyakul W. Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. World J Gastroenterol 2005; 11:2748-53. [PMID: 15884115 PMCID: PMC4305909 DOI: 10.3748/wjg.v11.i18.2748] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined.
METHODS: Five human CCA cell lines (KKU-100, KKU-M055, KKU-M156, KKU-M214 and KKU-OCA17) were treated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC50 values and the ratios of gene expression were analyzed by linear regression to predict their relationship.
RESULTS: Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC50 values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC50 values (<5 μmol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC50 values of etoposide, doxorubicin and pirarubicin (r = 0.86-0.98, P<0.05).
CONCLUSION: Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug sensitivity. MRP3 was correlated with resistance of CCA cell lines to etoposide, doxorubicin and pirarubicin, whereas other chemotherapeutic drugs showed no association. The role of this multidrug resistance-associated protein, MRP3, in chemotherapeutic resistance in CCA patients needs to be further investigated.
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Affiliation(s)
- Nisana Tepsiri
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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27
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Shen LZ, Hua YB, Yu XM, Xu Q, Chen T, Wang JH, Wu WX. Tamoxifen can reverse multidrug resistance of colorectal carcinoma in vivo. World J Gastroenterol 2005; 11:1060-4. [PMID: 15742416 PMCID: PMC4250773 DOI: 10.3748/wjg.v11.i7.1060] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of tamoxifen (TAM) on multidrug resistance (MDR) of colorectal carcinoma in vivo and its relationship with estrogen receptor (ER).
METHODS: Multidrug resistance was determined by means of semi-quantitative retro-transcription polymerase chain reaction (RT-PCR) to test mdr1 gene mRNA and ER expression was studied by immunohistochemistry. Tumor tissues from three cases of human colon carcinoma, which had mdr1(+)/ER(+), mdr1(+)/ER(-), mdr1(-) expressions, were planted subcutaneously in the neck of nude mice to establish three xenograft models. These models were subdivided into four subgroups randomly: Doxorubicin (DOX)-treated group, TAM-treated group, DOX and TAM group and control group. The dimensions of these xenografts were measured after each course of treatment and the xenografts were removed at the end of the experiments for measurements of weight and the variation of mdr1 mRNA level with RT-PCR. In each course, TAM [15 mg/(kg/d)] was administrated orally per day in the first seven days and DOX (3.6 mg/kg) was injected peritoneally on the first day. Data was evaluated by q and t tests.
RESULTS: In the animal models with mdr1(-) tumor, the weights and volumes of the planted tumor in DOX group [(39.1±2.29) mg, (31.44±1.61) mm3] and TAM and DOX group [(38.72±2.56) mg, (31.31±1.74) mm3], which were lesser than that of control group [(45.48±3.92) mg, (36.42±2.77) mm3, P = 0.037, P = 0.016 respectively] significantly. In the animal models with mdr1(+)/ER(+) tumor, the weights and volumes of planted tumor were not affected by DOX or TAM treatment; however, in TAM and DOX group [(425.5±28.58) mg, (340.35±22.28) mm3], they were significantly less than that of control group [(634.23±119.41) mg, (507.45±93.34) mm3, P = 0.022, P = 0.045 respectively], which are similar to that in the models with mdr1(+)/ER(-) tumor. No significant changes were found in the expressive level of mdr1 mRNA following these treatments.
CONCLUSION: The expression of mdr1 gene corresponds to the sensitivity of colon cancer to anti-tumor drugs in vivo. TAM can reverse the MDR of colorectal carcinoma in nude mice, which is independent of the expression of ER; however, no change was observed in the expressive level of mdr1 mRNA.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- Animals
- Antineoplastic Agents, Hormonal/pharmacology
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/physiopathology
- Drug Resistance, Multiple/drug effects
- Drug Resistance, Multiple/genetics
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- RNA, Messenger/analysis
- Receptors, Estrogen/genetics
- Tamoxifen/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Li-Zong Shen
- Department of Gastroenterology, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
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28
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Zhu Y, Kong C, Zeng Y, Sun Z, Gao H. Expression of lung resistance-related protein in transitional cell carcinoma of bladder. Urology 2004; 63:694-8. [PMID: 15072883 DOI: 10.1016/j.urology.2003.11.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2003] [Accepted: 11/12/2003] [Indexed: 01/12/2023]
Abstract
OBJECTIVES To determine the role of lung resistance-related protein (LRP) in intrinsic multidrug-resistance (MDR) of bladder cancer. METHODS The study group consisted of 66 patients with newly diagnosed primary bladder cancer. No patient had been treated preoperatively with either radiotherapy or chemotherapy. Reverse transcriptase-polymerase chain reaction was performed to measure LRP, multidrug resistance-associated protein 1 (MDR1), and MRP1 mRNA expression. The expression of LRP, p53 proteins, and p63 proteins was examined by immunohistochemistry. We analyzed the correlation of LRP with the above indexes and the clinical pathologic parameters. RESULTS The expression rate of LRP mRNA (63.6%) was the greatest among the three MDR markers in primary bladder cancer without exposure to chemotherapy. The LRP mRNA level was significantly greater in normal bladder tissue than in transitional cell carcinoma bladder tissue (P <0.01) and in superficial cancer than in invasive cancer (P = 0.013). LRP mRNA expression showed no association with either MDR1 or MRP1, but close correlation with the LRP level (P = 0.001). LRP was associated with low-grade (P <0.01) and low-stage (P <0.05) cancer but had no association with tumor suppressor p53 or p63. CONCLUSIONS The grade and stage-related expression pattern of LRP indicates that it may be a predictive index for intrinsic MDR in early bladder cancer. Anticancer drugs out of the MDR spectrum of LRP may be more effective for patients with early bladder cancer.
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Affiliation(s)
- Yuyan Zhu
- Department of Urology, First Clinical College and First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China
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