title: Enhanced cytotoxicity from deoxyguanosine-enriched T-oligo in prostate cancer cells.
abstract: Prostate cancer represents approximately 10 percent of all cancer cases in men and accounts for more than a quarter of all cancer types. Advances in understanding the molecular mechanisms of prostate cancer progression, however, have not translated well to the clinic. Patients with metastatic and hormone-refractory disease have only palliative options for treatment, as chemotherapy seldom produces durable or complete responses, highlighting the need for novel therapeutic approaches. T-oligo, a single-stranded deoxyribonucleic acid with partial sequence homology to human telomeric DNA, has elicited cytostatic and/or cytotoxic effects in multiple cancer cell types. In contrast, normal primary cells of varying tissue types are resistant to cytotoxic actions of T-oligo, underscoring its potential utility as a novel targeted cancer therapeutic. Mechanistically, T-oligo is hypothesized to interfere with normal telomeric structure and form G-quadruplex structures, thereby inducing genomic stress in addition to aberrant upregulation of DNA damageresponse pathways. Here, we present data demonstrating the enhanced effectiveness of a deoxyguanosine-enriched sequence of T-oligo, termed (GGTT)4, which elicits robust cytotoxic effects in prostate cancer cells at lower concentrations than the most recent T-oligo sequence (5'-pGGT TAG GTG TAG GTT T 3') described to date and used for comparison in this study, while exerting no cytotoxic actions on nontransformed human prostate epithelial cells. Additionally, we provide evidence supporting the T-oligo induced activation of cJun N-terminal kinase (JNK) signaling in prostate cancer cells consistent with G-quadruplex formation, thereby significantly advancing the understanding of the T-oligo mechanism of action.
authors: Cancer Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Andrew M
authors: AM
authors: Rankin
authors: Lora
authors: L
authors: Forman
authors: Sibaji
authors: S
authors: Sarkar
authors: Douglas V
authors: DV
authors: Faller
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000633:toxicity*; D004249:DNA Damage; D004277:DNA, Single-Stranded; D003849:Deoxyguanosine / Q000737:chemistry*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054856:G-Quadruplexes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009841:Oligonucleotides / Q000633:toxicity*; D009928:Organ Specificity; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016615:Telomere / Q000737:chemistry
chemical_list: D003603:Cytotoxins; D004277:DNA, Single-Stranded; D009841:Oligonucleotides; D048031:JNK Mitogen-Activated Protein Kinases; D003849:Deoxyguanosine
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