PMID- 28521363 OWN - NLM STAT- MEDLINE DCOM- 20170705 LR - 20180308 IS - 1460-2105 (Electronic) IS - 0027-8874 (Linking) VI - 109 IP - 10 DP - 2017 Oct 1 TI - A Cisplatin Derivative Tetra-Pt(bpy) as an Oncotherapeutic Agent for Targeting ALT Cancer. LID - 10.1093/jnci/djx061 [doi] 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 beta-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. CI - (c) The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. FAU - Zheng, Xiao-Hui AU - Zheng XH AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. AD - Sun Yat-sen University, Guangzhou, P. R. China; Medical School, Shenzhen University, Shenzhen, P. R. China. FAU - Nie, Xin AU - Nie X AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. FAU - Fang, Yiming AU - Fang Y AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. FAU - Zhang, Zepeng AU - Zhang Z AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. FAU - Xiao, Yingnan AU - Xiao Y AD - School of basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China. FAU - Mao, Zongwan AU - Mao Z AD - MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, P. R. China. FAU - Liu, Haiying AU - Liu H AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. FAU - Ren, Jian AU - Ren J AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. AD - Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, P. R. China. FAU - Wang, Feng AU - Wang F AD - School of basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. China. FAU - Xia, Lixin AU - Xia L AD - Sun Yat-sen University, Guangzhou, P. R. China; Medical School, Shenzhen University, Shenzhen, P. R. China. FAU - Huang, Junjiu AU - Huang J AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. FAU - Zhao, Yong AU - Zhao Y AD - Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. AD - Collaborative Innovation Center of High Performance Computing, National University of Defense Technology, Changsha, P. R. China. LA - eng PT - Journal Article PL - United States TA - J Natl Cancer Inst JT - Journal of the National Cancer Institute JID - 7503089 RN - 0 (Antineoplastic Agents) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Animals MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Cell Line, Tumor MH - Cisplatin/*analogs & derivatives/pharmacology MH - Female MH - Humans MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Molecular Targeted Therapy/*methods MH - Neoplasms/drug therapy/*genetics/pathology MH - Telomere/*drug effects MH - Telomere Homeostasis/*drug effects MH - Xenograft Model Antitumor Assays EDAT- 2017/05/19 06:00 MHDA- 2017/07/06 06:00 CRDT- 2017/05/19 06:00 PHST- 2016/10/14 00:00 [received] PHST- 2017/03/13 00:00 [accepted] PHST- 2017/05/19 06:00 [entrez] PHST- 2017/05/19 06:00 [pubmed] PHST- 2017/07/06 06:00 [medline] AID - 3752362 [pii] AID - 10.1093/jnci/djx061 [doi] PST - ppublish SO - J Natl Cancer Inst. 2017 Oct 1;109(10). doi: 10.1093/jnci/djx061.