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.
