A new tumor suppressor +Vitamin C?, Jack Roth is an author
Abstract Number: 5471
Presentation Title: Synergistic and selective inhibition of NSCLC cell growth via a caspase-independent cell death pathway by tumor suppressor 101F6 nanoparticles plus vitamin C in vitro and in vivo.
Presentation Start/End Time: Wednesday, Apr 05, 2006, 8:00 AM -12:00 PM
Location: Exhibit Hall, Washington Convention Center
Poster Section: 16
Poster Board Number: 5
Author Block: Shoichiro Ohtani, Kentaro Ueda, Gitanjali Jayachandran, Kai Xu, John D. Minna, Jack A. Roth, Lin Ji. M.D Anderson Cancer Center, Houston, TX, UT Southwestern Medical Center, Dallas, TX
101F6 is a candidate tumor suppressor gene on chromosome 3p21.3, a site of allele loss and genomic alterations were frequently found in many human cancers. We previously showed that enforced expression of wt-101F6 by adenoviral vector-mediated gene transfer significantly inhibited tumor cell growth in 3p21.3-deficient NSCLC cells in vitro and in vivo. How 101F6 exerts this effect is largely unknown. Using a computer-aided structural and functional modeling, we recently identified 101F6 as a member of the di-heme cytochrome b-561 protein family, which consists of a class of intrinsic high redox potential membrane proteins that are involved in the regeneration of ascorbate and may be important in diverse physiologic processes. We hypothesized that under normal physiologic conditions, 101F6 protects cells from antioxidative damage by regenerating antioxidant vitamin C and buffering deleterious oxidative stress and that in 101F6-deficient tumor cells, forced expression of wt-101F6 facilitates vitamin C-mediated cytotoxic H2O2 formation. To test these hypotheses, we examined endogenous 101F6 expression in human NSCLC cell lines and tissue samples. All normal lung bronchial epithelial cells (HBEC) and fibroblasts but less than 10% of lung cancers expressed 101F6. We investigated the combined effect of 101F6 and vitamin C on growth of HBEC and 3p21.3-deficient NSCLC cells: a nanoparticle-mediated wt-101F6 gene transfer plus a sub-pharmacologic concentration (IC20) of vitamin C synergistically inhibited NSCLC cell growth but did not affect normal cell growth in vitro. We also used a human NSCLC H322 orthotopic lung tumor xenograft mouse model to evaluate the therapeutic efficacy of systemic injection of 101F6 nanoparticles and intraperitoneal injection of vitamin C in vivo. Both the development and growth of lung tumors were synergistically inhibited by the combination treatment (P < 0.001). Furthermore, 101F6 facilitated the vitamin C-mediated formation and accumulation of H2O2 free radicals in the tumor cells, and these two agents synergistically killed the cells through caspase-independent apoptosis and autophagy cell death pathways. The synergistic and selective antitumor effect of 101F6 nanoparticles plus vitamin C may offer a tool for lung cancer prevention and intervention. This abstract is supported by grants from NCI (SPORE P50CA70907) and DOD (TARGET, DAMD17002-1-0706).
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