Novel DZ-SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. PDAC cell specific targeting of DZ-SIM is measured by determining the fluorescence in cells and animals. Mitochondrial bioenergetics and functions are measured by Seahorse and flow cytometry, respectively. Apoptosis is assessed by DNA fragmentation, annexin V/propidium iodide staining, and TUNEL. Markers of cell invasion, epithelial-to-mesenchymal transition, and cancer stemness are measured. The effect of DZ-SIM on survival, tumor growth, and metastasis is measured in the Kras( thorn /LSLG12D);Trp53( thorn /LSLR172H);Pdx-1(-Cre) transgenic mice and in syngeneic and subcutaneous PDAC models. NIR fluorescence imaging shows specific localization of DZ-SIM to cancer, but not to normal cells and tissues. DZ-SIM significantly inhibits tumor growth and re-sensitizes therapeutically resistant PDAC cells to conventional therapies. DZ-SIM kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics, including oxygen consumption and ATP production, and increasing ROS production. Mitochondrial depletion prevents the effect of DZ-SIM. Administration of DZ-SIM in three PDAC animal models results in a marked increase in survival and a decrease in tumor growth and metastasis.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. The drug significantly inhibits tumor growth, re-sensitizes therapeutically resistant PDAC cells to conventional therapies, and kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics and increasing ROS production.