Abstract 1007: Nanoformulation enhances anti-angiogenic efficacy of Tunicamycin

Abstract

Abstract The breast cancer landscape indicates it is a global problem and accounts for nearly a quarter of all cancers in women. In 2008, 1.4 million women were diagnosed with the disease worldwide and 438,000 died globally in 2010. In the United States, it is estimated that 296,000 women and 2,240 men will be diagnosed with breast cancer in 2013 and 39,620 women and 410 men will die from the disease. In 2030, with no major changes in prevention or treatment 747,802 women are estimated to die worldwide. Breast cancer treatment includes surgery, radiation therapy, chemotherapy and/or hormonal therapy, and within the past 15 years, targeted antibody therapy. Unfortunately, de novo and acquired resistance are major issues with all known targeted therapies. Tumor microenvironment (TME) is immensely complex and contributes to chemoresistance. Using Tunicamycin, a potent inhibitor of asparagine-linked (N-linked) protein glycosylation we have established earlier that Tunicamycin inhibits (i) angiogenesis in vitro by arresting cells in G1; (ii) in vivo angiogenesis in Matrigel™ implant in nude mice; and (iii) prevents the progression of double- and triple-negative breast tumors in athymic nude mice by inducing “ER stress”. Nanoparticles (<100 nm) evade the immune system's clearing mechanisms long enough to reach the targeted disease tissue efficiently. We have, therefore, hypothesized that nano-formulated Tunicamycin would have a better efficacy in treating breast cancer in the clinic. The objective was to evaluate nano-formulated Tunicamycin, and we have used Tunicamycin encapsulated in peptide nanotubes, nanotubes bound to gold nanoparticles (Au NPs) conjugated with Tunicamycin, Tunicamycin conjugated with nanotubes, Au NPs bound to tubes and conjugated with Tunicamycin, and Au NPs conjugated with Tunicamycin. The MTT assay indicated that nanoparticles (1 μg/mL) inhibited capillary endothelial cells proliferation ∼50% within one hour of treatment whereas the native Tunicamycin had no effect. The nanoformulated Tunicamycin blocked the cell cycle progression by inhibiting either both cyclin D1 and CDK4, or cyclin D1, or the CDK4 expression as well as the expression of phospho Rb (serine-229/threonine-252). Phosphorylation of p53 at serine-392 was down-regulated but not the total p53. Increased expression of GRP-78/Bip identified “ER stress”. Upregulated expression (1.6-5.5 folds) of phopsho-PERK supported induction of unfolded protein response (upr) signaling. Down regulated expression of caspase-9 and caspase-3 proposes a non-canonical pathway of cell death during “ER stress” induced by nano-formulated Tunicamycin. Citation Format: Aditi Banerjee, Dipak K. Banerjee. Nanoformulation enhances anti-angiogenic efficacy of Tunicamycin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1007. doi:10.1158/1538-7445.AM2014-1007