Chad Darnell, “Anti-Tumor Mechanisms of Mitochondria Targeted Compounds”
Mentor: Mike Dwinell, MCW Cancer Center
Poster #90
In the United States pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death with a five-year survival rate of ~10%. PDAC is highly resistant to radiation and chemical therapies, including immune therapies. New therapeutic approaches focus on targeting PDACs energy metabolism system to disrupt tumor progression with the use mitochondria-targeted inhibitors mito-metformin (MMe) and Fluorinated mito-metformin (FlMMe). These analogues possess the capability to preferentially accumulate within cancer cells and disrupt mitochondrial respiration. Published data from the laboratory indicate that MMe and FlMMe decrease mitochondrial respiration, inhibit complex I, and thereby decrease overall ATP levels. MMe has shown promise at inhibiting growth both in vitro and in vivo. Although 1000x more selective than its parent compound Metformin, MMe is not easily trackable. Our novel analogue FlMMe has proven to be more cancer selective, and safer, maintaining the same functional capacity while increasing detectability in vitro and in vivo. We asked if MMe and FlMMe anti-tumor effects were mediated through comparable molecular mechanisms. We hypothesized that inhibition of OXPHOS energy metabolism with mitochondria-targeted inhibitors inhibits cell proliferation and stimulates apoptosis in PDAC cell lines. We measured the antiproliferative and apoptotic effect initiated by MMe and FlMMe in a dose dependent manner via the Incucyte Live-Cell Analysis system. Using the Incucyte system we simultaneously measured changes in confluency as a surrogate for cellular proliferation and activity of the apoptosis effector caspases 3/7 in treated PDAC cells. We measured a statistically significant increase in apoptosis followed temporally by decreased cell proliferation. Moreover, we determined that FlMMe has a greater apoptotic effect on PDAC compared to MMe in both mouse and human PDAC cells. Therefore, the progressive development of TPP+ conjugated mitochondria targeted inhibitors may lead to new immunotherapeutic treatment options in PDAC.