2 research outputs found
Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells
Achiral Mannich-type curcumin analogs have been synthetized and assayed for their
cytotoxic activity. The anti-proliferative and cytotoxic activity of curcuminoids has been tested on
human non-small-cell lung carcinoma (A549), hepatocellular carcinoma (HepG2) and pancreatic
cancer cell line (PANC-1). Based on the highest anti-proliferative activity nine drug candidates
were further tested and proved to cause phosphatidylserine exposure as an early sign of apoptosis.
Curcumin analogs with the highest apoptotic activity were selected for mechanistic studies in
the most sensitive PANC-1 cells. Cytotoxic activity was accompanied by cytostatic effect since
curcumin and analogs treatment led to G0/G1 cell cycle arrest. Moreover, cytotoxic effect could
be also detected via the accumulation of curcuminoids in the endoplasmic reticulum (ER) and
the up-regulation of ER stress-related unfolded protein response (UPR) genes: HSPA5, ATF4,
XBP1, and DDIT3. The activated UPR induced mitochondrial membrane depolarization, caspase-3
activation and subsequent DNA breakdown in PANC-1 cells. Achiral curcumin analogs, C509,
C521 and C524 possessed superior, 40-times more potent cytotoxic activity compared to natural
dihydroxy-dimetoxycurcumin in PANC-1 cells