Features that determine telomere homolog oligonucleotide-induced therapeutic DNA damage-like responses in cancer cells.
Cancer is the second leading cause of death in the USA, with metastatic disease proving a particular management challenge. Treatment modalities for patients with metastatic disease are limited, and survival beyond 5 years is uncommon. We have reported that an 11-base DNA oligonucleotide 100% homologous to the telomere 3' overhang can induce apoptosis, senescence and/or differentiation of several types of malignant cells in vitro and in vivo, while having minimal effect on normal cells. We now report that 22 oligonucleotides, 9-20 bases in length, with or without a 5' phosphate group and with varying homology (40-100%) to the 3' overhang, inhibit growth and induce apoptosis of human cell lines derived from breast cancers, pancreatic and ovarian carcinomas, and malignant melanoma, lines that lack p53 and/or p16 and harbor a variety of other abnormalities in key regulatory signaling pathways. Cytosine (C) content adversely affected oligonucleotide efficacy, decreasing their effect on cellular apoptosis by > or =80%. These data confirm and expand our earlier work suggesting that such telomere homolog oligonucleotides (T-oligos) target an innate anti-cancer defense system in human cells and may provide an effective treatment for cancers of multiple different cellular origins and genetic profile.
Ohashi
Norio
N
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.
Yaar
Mina
M
Eller
Mark S
MS
Truzzi
Francesca
F
Gilchrest
Barbara A
BA
D000375:Aging / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004249:DNA Damage / Q000235:genetics*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D016615:Telomere / Q000235:genetics*
D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones; D009841:Oligonucleotides