Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. We have developed a novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (HMCD), and HMG-CoA inhibitor simvastatin (SIM), and assessed its efficacy in PDAC. PDAC cell specific targeting of DZ-SIM was measured by determining the fluorescence in cells and animals. Mitochondrial bioenergetics and functions were measured by Seahorse and flow cytometry, respectively. Apoptosis was assessed by DNA fragmentation, AnnexinV/Propidium Iodide staining, and TUNEL. Markers of cell invasion, epithelial-to-mesenchymal transition, and cancer stemness were measured. The effect of DZ-SIM on survival, tumor growth and metastasis was measured in the Kras þ/LSLG12D ;Trp53 þ/LSLR172H ;Pdx-1 -Cre (KPC) transgenic mice and in syngeneic and subcutaneous PDAC models. NIR fluorescence imaging showed specific localization of DZ-SIM to cancer, but not to normal cells and tissues. DZ-SIM significantly inhibited tumor growth and re-sensitized therapeutically resistant PDAC cells to conventional therapies. DZ-SIM killed cancer cells through unique pathways involving decreasing mitochondrial bioenergetics, including oxygen consumption and ATP production, and increasing ROS production. Mitochondrial depletion prevented the effect of DZ-SIM. Administration of DZ-SIM in 3 PDAC animal models resulted in a marked increase in survival and a decrease in tumor growth and metastasis.
Keyphrases
- cell cycle arrest
- induced apoptosis
- fluorescence imaging
- oxidative stress
- cell death
- papillary thyroid
- flow cytometry
- endoplasmic reticulum stress
- photodynamic therapy
- squamous cell
- cancer therapy
- stem cells
- pi k akt
- dna damage
- small molecule
- single cell
- squamous cell carcinoma
- bone marrow
- fluorescent probe
- cell free
- wild type