Genomic c-Myc quadruplex DNA selectively kills leukemia

• Published in: Molecular cancer therapeutics 2012-01, Vol.11 (1), p.66-76
• Main Authors: Sedoris, Kara C, Thomas, Shelia D, Clarkson, Cortney R, Muench, David, Islam, Ashraful, Singh, Rajesh, Miller, Donald M
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Cell Cycle - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor - drug effects; Cell Proliferation - drug effects; G-Quadruplexes; Humans; Leukemia - metabolism; Leukemia - pathology; Mitochondria - drug effects; Mitochondria - pathology; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Transcription, Genetic
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0515

c-Myc, a key regulator of cell cycle and proliferation, is commonly overexpressed in leukemia and associated with poor prognosis. Conventional antisense oligonucleotides targeting c-myc may attenuate leukemic cell growth, however, are poorly taken into cells, rapidly degraded, and have unwanted effects on normal cells. The c-myc promoter contains a guanine-rich sequence (PU27) capable of forming quadruplex (four-stranded) DNA, which may negatively regulate c-myc transcription. However, its biological significance is unknown. We show that treatment of leukemia with an oligonucleotide encoding the genomic PU27 sequence induces cell-cycle arrest and death by oncotic necrosis due to PU27-mediated suppression of c-myc mRNA/protein expression. Furthermore, PU27 is abundantly taken into cells, localized in the cytoplasm/nucleus, inherently stable in serum and intracellularly, and has no effect on normal cells. Suppression of c-myc expression by PU27 caused significant DNA damage, cell and mitochondrial swelling, and membrane permeability characteristic of oncotic necrosis. Induction of oncosis caused mitochondrial dysfunction, depletion of cellular ATP levels, and enhanced oxidative stress. This novel antileukemic strategy addresses current concerns of oligonucleotide therapeutics including problems with uptake, stability, and unintentional effects on normal cells and is the first report of selective cancer cell killing by a genomic DNA sequence.