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Neelu Puri

Neelu Puri

University of Illinois at Urbana, USA

Title: Therapeutic potential of T-Oligo and its mechanism of action

Biography

Neelu Puri’s expertise is in the area of thoracic and skin oncology in both translational and basic sciences. Her main research interest is to study novel targeted therapeutics to enhance the quality of life and survival of patients with cancer. She is also investigating obesity which is a major health problem worldwide. Her laboratory investigates the mechanism of action of FTO a newly discovered gene which causes obesity in humans.

Abstract

On telomere disruption, exposure of single stranded telomere 3' overhang triggers DNA damage pathways resulting in cell senescence and apoptosis. T-oligo, an oligonucleotide homologous to the 3' overhang, mimics telomere exposure inducing p53/p73 associated damage responses in malignant cells. NSCLC tumors in nude mice treated with T-oligo by intratumoral injections (60 nmoles) for 6 weeks exhibited a 5.6 and 4.3 fold reduction in size respectively. β-galactosidase examination exhibited strong staining for senescence in H358 and SW1573 tumors. Angiogenesis and vasculogenesis staining in H358 and SW1573 displayed 2.2 fold and 3 fold reduction, respectively. Additionally, IV T-oligo reduced melanoma tumors by 3.7 suggesting that T-oligo maybe a molecularly targeted cancer therapy. To increase the stability of negatively charged T-oligo, it was complexed with increasing concentration of a nano-sized cationic α-helical polypeptide and transfected into H358 lung cancer and AN melanoma cells, it inhibited cell growth in a dose responsive manner from 3.3-6.6 and 4.5-8.3 fold respectively in vitro. Ongoing in vivo studies indicate that this peptide enhances the antitumor efficacy of T-oligo. Immunoblots of TRF 1 and 2, proteins associated with the protective telomere T-loop structure, showed 1.7 fold downregulation of TRF1 and 2.6 fold upregulation of TRF-2 after treatment with T-oligo. Tankyrase-1 aids in increasing telomere length and we found a combination of T-oligo and XAV939, a tankyrase inhibitor had minimal effect on TRF1 but reduced upregulation in TRF-2 suggesting that T-oligo may only stabilize part of the free shelterin complex and tankyrase-1 maybe involved in T-oligo mediated signaling.

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