Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells
by
Gábor J. Szebeni 1,2
, Árpád Balázs 1, Ildikó Madarász 1, Gábor Pócz 1, Ferhan Ayaydin 3, Iván Kanizsai 1, Roberta Fajka-Boja 4, Róbert Alföldi 1, László Hackler Jr. 1,2 and László G. Puskás 1,2,*
Gábor J. Szebeni 1,2, Árpád Balázs 1, Ildikó Madarász 1, Gábor Pócz 1, Ferhan Ayaydin 3, Iván Kanizsai 1, Roberta Fajka-Boja 4, Róbert Alföldi 1, László Hackler Jr. 1,2 and László G. Puskás 1,2,*
1
Avidin Ltd., Alsó kikötő sor 11/D, H-6726 Szeged, Hungary
2
Laboratory of Functional Genomics, Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, H-6726 Szeged, Hungary
3
Cellular Imaging Laboratory, Institute of Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, H-6726 Szeged, Hungary
4
Artificial Chromosome and Stem Cell Research Laboratory, Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, H-6726 Szeged, Hungary
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(10), 2105; https://doi.org/10.3390/ijms18102105
Received: 26 September 2017 / Revised: 3 October 2017 / Accepted: 3 October 2017 / Published: 7 October 2017
(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)
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.
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Keywords:
curcumin; endoplasmic reticulum stress; unfolded protein response; mitochondrial depolarization; caspase-3; apoptosis
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MDPI and ACS Style
Szebeni, G.J.; Balázs, Á.; Madarász, I.; Pócz, G.; Ayaydin, F.; Kanizsai, I.; Fajka-Boja, R.; Alföldi, R.; Hackler Jr., L.; Puskás, L.G. Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells. Int. J. Mol. Sci. 2017, 18, 2105.
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