Abstract 1500: Evaluating the efficacy of limiting heme availability on growth and progression of lung tumor

Numerous studies support the importance of mitochondrial respiration in tumorigenesis. Studies from our lab have demonstrated that mitochondrial respiration is intensified, and the levels of intracellular heme and hemoproteins are elevated in Non-small cell lung cancer (NSCLC) cells. We also demonstrated that lowering intracellular heme levels selectively decreases oxygen consumption in NSCLC cells and inhibits cell migration and colony formation. Heme is a central molecule for mitochondrial function and for all processes involved in oxygen utilization. It serves as a prosthetic group in several oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Most human cells can synthesize heme de novo and uptake heme from the circulation. Further, a number of epidemiological studies have shown that high heme intake is associated with increased risk of several cancers, including lung cancer. The purpose of the study is to determine the extent to which altering heme availability impacts NSCLC tumor growth and development. To this end, we devised a two-pronged approach to target both heme intake and heme synthesis to limit the heme available to cells. Our lab synthesized a peptide to sequester heme from circulation and thereby limit heme available for uptake. A well-known inhibitor of heme synthesis is used to limit heme synthesis. NSCLC cells that express luciferase were implanted in NOD/SCID mice to generate subcutaneous and lung orthotopic xenografts. The mice were treated with the peptide alone and in combination with an inhibitor. The tumor growth was monitored by non-invasive bioluminescence imaging (BLI) using Perkin Elmer’s IVIS Lumina III Imager. In subcutaneously implanted xenografts, our BLI data show that there is a considerable reduction in radiance (total flux in photons per second) in the treatment groups that received the peptide and a combination of peptide and inhibitor. This trend was also observed in tumor volumes measured by calipers. This observation is further corroborated in lung orthotopic xenografts, where there is a significant reduction in radiance in the treatment groups that received the peptide and peptide-inhibitor combination. In all the cases the combination of the peptide and the inhibitor had a greater effect than the peptide alone. Our results indicate that combination of heme lowering agents works effectively in limiting lung tumor growth and progression by limiting both heme uptake and synthesis. Further stud