دورية أكاديمية
Therapeutic Targeting of ATP7B in Ovarian Carcinoma.
| العنوان: | Therapeutic Targeting of ATP7B in Ovarian Carcinoma. |
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| المؤلفون: | Mangala LS; Departments of Gynecologic Oncology, Experimental Therapeutics, and Cancer Biology, The University of Texas M. D. Anderson Cancer Center, USA., Zuzel V, Schmandt R, Leshane ES, Halder JB, Armaiz-Pena GN, Spannuth WA, Tanaka T, Shahzad MM, Lin YG, Nick AM, Danes CG, Lee JW, Jennings NB, Vivas-Mejia PE, Wolf JK, Coleman RL, Siddik ZH, Lopez-Berestein G, Lutsenko S, Sood AK |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2009 Jun 01; Vol. 15 (11), pp. 3770-80. Date of Electronic Publication: 2009 May 26. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1078-0432 (Print) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | RNA Interference* , Xenograft Model Antitumor Assays*, Adenosine Triphosphatases/*metabolism , Cation Transport Proteins/*metabolism , Ovarian Neoplasms/*therapy, Adenosine Triphosphatases/genetics ; Animals ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Apoptosis ; Binding Sites ; Blotting, Western ; Cation Transport Proteins/genetics ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/drug effects ; Cisplatin/metabolism ; Cisplatin/pharmacology ; Copper-Transporting ATPases ; DNA Adducts/drug effects ; Drug Resistance, Neoplasm/genetics ; Female ; Humans ; Immunohistochemistry ; Mice ; Mice, Nude ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Protein Binding ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Burden |
| مستخلص: | Purpose: Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models. Experimental Design: Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). Results: ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC(50) levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH(2)-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis. Conclusion: These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance. |
| التعليقات: | Expression of concern in: Clin Cancer Res. 2021 Aug 1;27(15):4454. (PMID: 34341059) |
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| معلومات مُعتمدة: | T32 CA101642 United States CA NCI NIH HHS; P30 CA016672 United States CA NCI NIH HHS; HD050128 United States HD NICHD NIH HHS; F31CA126474 United States CA NCI NIH HHS; CA16672 United States CA NCI NIH HHS; DK071865 United States DK NIDDK NIH HHS; R01 DK071865 United States DK NIDDK NIH HHS; F31 CA126474 United States CA NCI NIH HHS; P50 CA083639 United States CA NCI NIH HHS; P50 CA083639-090008 United States CA NCI NIH HHS; P50 CA 083639 United States CA NCI NIH HHS; R56 DK071865 United States DK NIDDK NIH HHS; K12 HD050128 United States HD NICHD NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Cation Transport Proteins) 0 (DNA Adducts) EC 3.6.1.- (Adenosine Triphosphatases) EC 7.2.2.8 (ATP7A protein, human) EC 7.2.2.8 (ATP7B protein, human) EC 7.2.2.8 (Copper-Transporting ATPases) Q20Q21Q62J (Cisplatin) |
| تواريخ الأحداث: | Date Created: 20090528 Date Completed: 20090707 Latest Revision: 20211020 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC2752981 |
| DOI: | 10.1158/1078-0432.CCR-08-2306 |
| PMID: | 19470734 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1078-0432 |
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| DOI: | 10.1158/1078-0432.CCR-08-2306 |