A Cisplatin Derivative Tetra-Pt(bpy) as an Oncotherapeutic Agent for Targeting ALT Cancer.
Background: In approximately 15% of human cancers, telomere length is maintained independently of telomerase by the homologous recombination (HR)-mediated alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for therapeutic treatment remains unknown. The purpo...
| Publicado en: | JNCI: Journal of the National Cancer Institute Vol. 109; no. 10; pp. 1 - 12 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Oxford University Press / USA
Oct2017
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=123323462&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 123323462 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00278874 JNC jtl: JNCI: Journal of the National Cancer Institute issn: 00278874 maglogo: N pubinfo: dt: Oct2017 vid: 109 iid: 10 pid: 622 pub: Oxford University Press / USA artinfo: ui: 123323462 123323462 NLM28521363 123323462 10.1093/jnci/djx061 NLM28521363 123323462 ppf: 1 ppct: 11 formats: tig: atl: A Cisplatin Derivative Tetra-Pt(bpy) as an Oncotherapeutic Agent for Targeting ALT Cancer. aug: au: Xiao-hui Zheng Xin Nie Yiming Fang Zepeng Zhang Yingnan Xiao Zongwan Mao Haiying Liu Jian Ren Feng Wang Lixin Xia Junjiu Huang Yong Zhao Zheng, Xiao-Hui Nie, Xin Fang, Yiming Zhang, Zepeng Xiao, Yingnan Mao, Zongwan Liu, Haiying Ren, Jian affil: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China sug: subj: Neoplasms Cell Division Drug Effects Cisplatin Analogs and Derivatives Drug Therapy Methods Antineoplastic Agents Pharmacodynamics Telomere Drug Effects Mice Antineoplastic Agents Therapeutic Use Cell Line, Tumor Female Cisplatin Pharmacodynamics Neoplasms Pathology Animals Neoplasms Drug Therapy Human Animal Studies Molecular Structure Female ab: Background: In approximately 15% of human cancers, telomere length is maintained independently of telomerase by the homologous recombination (HR)-mediated alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for therapeutic treatment remains unknown. The purpose of this study is to develop oncotherapeutic agent to target ALT cancers.Methods: Surface plasmon resonance assay, antibody to G-quadruplex, and fluorescence in situ hybridization (FISH) were used to discover Tetra-Pt(bpy), a cisplatin derivative that specifically targets telomeric G-quadruplex. We used immunofluorescence, FISH, C-circle assay, and chromosome orientation FISH to evaluate the inhibitory effect of Tetra-Pt(bpy) on ALT activity in human ALT cancers. The shortening of telomere length induced by Tetra-Pt(bpy) was determined by telomere restriction fragment or Q-FISH. Cell destination after Tetra-Pt(bpy) treatment was determined by β-gal staining or apoptosis assay. Nude mice (n = 4 per group) were injected with U2OS cells to evaluate the effects of Tetra-Pt(bpy) on tumor growth. All statistical tests were two-sided.Results: Tetra-Pt(bpy) inhibits the strand invasion/annealing step of telomeric homologous recombination by selectively converting telomeric ssDNA to a G-quadruplex. ALT-cells treated with Tetra-Pt(bpy) show fewer ALT-associated promyelocytic leukemia bodies (untreated: mean±SD = 5.9±0.2 vs treated: mean±SD = 3.1±0.1, P < .001), fewer extrachromosomal C-circles (untreated: mean±SD = 100.5±1.6 vs treated: mean±SD = 18.0±1.7, P < .001), and reduced telomere sister chromatin exchanges (untreated: mean±SD = 25.2%±1.5% vs treated: mean±SD = 13.1%±1.9%, P < .001). Consequently, critically short telomeres accumulate after multiple population doublings (untreated: mean±SD = 18.9%±1.7% vs treated: mean±SD = 57.4%±2.2%, P < .001), resulting in cell death by apoptosis or senescence. In vivo, Tetra-Pt(bpy) severely inhibits the growth of ALT-cell xenograft tumors in mice (untreated: mean±SD = 57.1±3.7 mm 3 vs treated: mean±SD = 19.0±3.2 mm 3 , P < .001). Importantly, Tetra-Pt(bpy) exhibits no adverse effects on proliferation, gene expression, or telomere metabolism in normal cells.Conclusions: These results reveal the potential of Tetra-Pt(bpy) as a novel oncotherapeutic agent for targeting ALT cancer cells. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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