title: MST-312 Alters Telomere Dynamics, Gene Expression Profiles and Growth in Human Breast Cancer Cells.
abstract: BACKGROUND
  Targeting telomerase is a potential cancer management strategy given that it allows unlimited cellular replication in the majority of cancers. Dysfunctional telomeres are recognized as double-strand breaks. However, the status of DNA repair response pathways following telomerase inhibition is not well understood in human breast cancer cells. Here, we evaluated the effects of MST-312, a chemically modified derivative from tea catechin, epigallocatechin gallate, on telomere dynamics and DNA damage gene expression in breast cancer cells.
  
  
  METHODS
  Breast cancer cells MCF-7 and MDA-MB-231 were treated with MST-312, and telomere-telomerase homeostasis, induced DNA damage and gene expression profiling were analyzed.
  
  
  RESULTS
  MST-312 decreased telomerase activity and induced telomere dysfunction and growth arrest in breast cancer cells with more profound effects in MDA-MB-231 than in MCF-7 cells. Consistent with these data, the telomere-protective protein TRF2 was downregulated in MDA-MB-231 cells. MST-312 induced DNA damage at telomeres accompanied by reduced expression of DNA damage-related genes ATM and RAD50. Co-treatment with MST-312 and the poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor PJ-34 further enhanced growth reduction as compared to single treatment with MST-312 or PJ-34.
  
  
  CONCLUSIONS
  Our work demonstrates potential importance for the establishment of antitelomerase cancer therapy using MST-312 along with PARP-1 inhibition in breast cancer therapy.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Resham Lal
authors.initials: RL
authors.lastname: Gurung
authors.forename: Shi Ni
authors.initials: SN
authors.lastname: Lim
authors.forename: Grace Kah Mun
authors.initials: GK
authors.lastname: Low
authors.forename: M Prakash
authors.initials: MP
authors.lastname: Hande
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D054647:Nutrigenomics; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D059767:Recombinational DNA Repair / Q000187:drug effects / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000187:drug effects* / Q000235:genetics; D059506:Telomere Shortening / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C470197:MST 312; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019098:Telomerase