Abstract
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.
Highlights
Turmeric spice obtained from the rhizomes of Curcuma longa has been used for centuries in traditional Chinese medicine and in Ayurveda in India based on its assumed anti-inflammatory, anti-microbial, and anti-cancer effects [1]
We report the cytotoxic activity of the achiral curcumin analog library analogs [15,16,17]
In order to clarify whether the viability of A549, HepG2, and PANC-1 cells was hampered by apoptosis or necrosis, we carried out annexin V-propidium iodide (PI) staining on the cells treated by nine the selected nine selected candidates
Summary
Turmeric spice obtained from the rhizomes of Curcuma longa has been used for centuries in traditional Chinese medicine and in Ayurveda in India based on its assumed anti-inflammatory, anti-microbial, and anti-cancer effects [1]. Curcuminoids make up 2–5% of turmeric powder and consist of dihidroxy-dimetoxycurcumin (curcumin, 77%), mono-demethoxycurcumin (17%) and bis-demethoxycurcumin (3%) [2]. Due to the empirical beneficial health effect of turmeric the consumption of curcumin as a dietary supplement increased worldwide. Curcumin has been designated “Generally Recognized as Safe (GRAS)” by the Food and Drug Administration of.
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