title: The telomere-binding protein TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.
abstract: Gemcitabine and capecitabine are two effective anticancer agents against solid tumors. The pharmacological mechanisms have been known as incorporation into DNA and thereby inhibition of DNA synthesis. When used as metronomic chemotherapy, they may inhibit angiogenesis and induce immunity. In our previous study, we showed that low-dose gemcitabine caused telomere shortening by stabilizing TRF2 that was required for XPF-dependent telomere loss. In this report, we established a SKOV3.ip1 ascites cell model. Tumor-bearing mice were treated with low-dose gemcitabine (GEM) or capecitabine (CAP). Both GEM and CAP caused telomere shortening and increased expression of TRF2 with improved ascites in nude mice and decreased in vitro clonogenic activity. TRF2 knockdown altered telomeres to a shortened but new status that may evade XPF-dependent telomere loss and conferred resistance of SKOV3.ip1 ascites cells to low-dose GEM and CAP. Our study provides a new mechanism of metronomic chemotherapy i.e. TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan. Electronic address: wplee@vghtpe.gov.tw.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Medicine Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Keng-Hsin
authors.initials: KH
authors.lastname: Lan
authors.affiliation: Department of Medicine Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.affiliation: Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Department of Medicine Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Hou
authors.affiliation: Department of Medicine Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Department of Medicine Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000069287:Capecitabine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis / Q000187:drug effects* / Q000235:genetics; D035341:Telomeric Repeat Binding Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D009363:Neoplasm Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D003841:Deoxycytidine; D000069287:Capecitabine; D000093542:Gemcitabine
keywords: Metronomic chemotherapy; TRF2; Telomere