Apoptosis-promoting autophagy mediates anti-migratory effects of unsymmetrical bisacridines in pancreatic cancer cells.

Pancreatic cancer (PC) remains one of the most lethal malignancies, underscoring the urgent need for new therapeutic strategies. Our previous studies demonstrated that unsymmetrical bisacridines (UAs) exhibit strong anticancer activity against PC cells by inducing apoptosis. Given the complex role of autophagy in tumor progression, particularly its association with poor prognosis in PC, this study aimed to evaluate the effects of UAs on autophagy and its crosstalk with apoptosis and migration in PC cells. Three UA derivatives (C-2028, C-2045, and C-2053) were tested on pancreatic cancer (Panc-1, MIA PaCa-2, AsPC-1, BxPC-3), and normal (hTERT-HPNE) cell lines. The biological evaluation included assessment of cell viability (MTT), apoptosis (Annexin V-FITC, caspase 3/7, and nuclear staining), and autophagy (acidic vesicular organelles staining and molecular markers). Cell migration and related molecular markers were also analyzed. UAs exhibited markedly greater cytotoxicity and induced substantially higher levels of apoptosis in pancreatic cancer cells compared to normal cells. UAs triggered increased autophagic flux in a cell line-dependent and Beclin1-independent manner. The interplay between autophagy and apoptosis was complex but predominantly pro-death. All UAs significantly inhibited PC cell migration, with antimigratory effects linked to autophagic activity. These findings demonstrate that UAs exert a dual pro-apoptotic and anti-migratory effect on PC cells through autophagy. Their selective activity and limited toxicity toward normal pancreatic cells support further development of UA derivatives as promising therapeutic candidates for pancreatic cancer.