Telomere-based DNA damage responses: a new approach to melanoma NEELU PURI 1 , MARK S. ELLER, H. RANDOLPH BYERS, SARAH DYKSTRA, JOHN KUBERA and BARBARA A. GILCHREST 2 Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA 2 Correspondence: Department of Dermatology, Boston University School of Medicine, 609 Albany St., J-Bldg., Boston, MA 02118-2394, USA. E-mail: bgilchre@bu.edu Melanoma is the most fatal skin cancer, often highly resistant to chemotherapy. Here we show that treatment with an 11-base DNA oligonucleotide homologous to the telomere 3' overhang sequence (T-oligo) induces apoptosis of several established human melanoma cell lines, including the aggressive MM-AN line, whereas normal human melanocytes exposed to the same or higher T-oligo concentrations show only transient cell cycle arrest, implying that malignant cells are more sensitive to T-oligo effects. When MM-AN cells were briefly exposed to T-oligo in culture and injected into the flank or tail vein of SCID mice, eventual tumor volume and number of metastases were reduced 85–95% compared with control mice. Similarly, T-oligos administered intralesionally or systemically selectively inhibited the growth of previously established MM-AN tumor nodules in the flank and peritoneal cavity by 85 to 90% without detectable toxicity. We previously showed that T-oligos act through ATM, p95/Nbs1, E2F1, p16 INK4A , p53, and the p53 homologue p73 to modulate downstream effectors and now additionally demonstrate striking down-regulation of the inhibitor of apoptosis protein livin/ML-IAP. We suggest that T-oligo mimics a physiologic DNA damage signal that is frequently masked in malignant cells and thereby activates innate cancer prevention responses. T-oligos may provide a novel therapeutic approach to melanoma.—Puri, N., Eller, M. S., Byers, H. R., Dykstra, S., Kubera, J., Gilchrest, B. A. Telomere-based DNA damage responses: a new approach to melanoma. Key Words: melanocyte • apoptosis • differentiation • p73 • livin/ML-IAP
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Telomere-based DNA damage responses: a new approach to melanoma
PURI, NEELU; ELLER, MARK S.; BYERS, H. RANDOLPH; DYKSTRA, SARAH; KUBERA, JOHN; GILCHREST, BARBARA A.
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, Volume 18 (12): 1373
Fed of American Socs for Experimental Biology – Sep 1, 2004
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