Antitumor 1‐nitroacridine, C‐1748, Decreases Pro‐survival Autophagy and Induces Accumulation of Lipid Droplets Resulting in Apoptosis of Panc‐1 Pancreatic Cancer Cells

Abstract

Given poor prognosis of pancreatic cancer, there is a strong need for the development of novel therapeutic agents and discovery of new molecular targets. Changes in lipid metabolism can affect numerous cellular processes, including cancer cell growth, proliferation or differentiation. Here, we show for the first time that DNA‐damaging antitumor agent, C‐1748, affects lipid content in pancreatic cancer Panc‐1 cells which may contribute to its antiproliferative effect. Cytotoxic activity of C‐1748 against Panc‐1 cells was similar to clinically used gemcitabine. Compared with unexposed cells, C‐1748 reduced level of pro‐survival autophagy as shown by decrease in Acidic Vesicular Organelles. Staining with Nile Red showed that inhibition of autophagy was accompanied by accumulation of cytosolic lipid droplets (LDs). The pool of LDs following C‐1748 treatment increased in a dose‐ and time‐dependent manner. Importantly, along with decreased autophagy and development of LDs, C‐1748 progressively triggered mitochondrial dysfunction, caspase‐3 activation indicating on induction of apoptotic cell death. Recent studies indicate that autophagy allows cancer cells to maintain energy supply during stress conditions, and inhibition of autophagy increases triglyceride storage in LDs, what prevents them from being used as energy source. Our study suggests that C‐1748 blocks autophagy in pancreatic cancer cells, which disrupts pro‐survival lipid metabolism and leads to cell death.