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Induction of Apoptosis and Generation of Reactive Oxygen Species by Novel Chalcone Derivatives
Author(s) -
Stang Christopher R.T.,
Adams Bryce R.,
Faler Ashton D.,
Schuler Brian R.,
Eichel Amanda M.,
Dick Matt J.,
Orahood Cassandra B.,
Whited Tawna L.,
Rao P.S.S.,
Dudley Richard W.,
Khupse Rahul S.,
Schneider Ryan A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.670.10
Subject(s) - chalcone , apoptosis , chemistry , reactive oxygen species , cell culture , flavanone , programmed cell death , caspase 3 , cancer cell , cancer research , microbiology and biotechnology , biochemistry , flavonoid , cancer , biology , stereochemistry , genetics , antioxidant
The presence of alpha‐beta unsaturated systems in naturally occurring flavonoids has been attributed to a diverse array of physiological activities. We previously reported on the anti‐cancer activity of several chalcone and flavanone derivatives from our small flavonoid library. Here we present the anti‐cancer effects of our two newest chalcone derivatives, RK15 and RK19, in four diverse human cancer cell lines: A‐172 glioblastoma, A375 melanoma, HT‐29 colon carcinoma, and MCF7 breast adenocarcinoma. The XTT cell proliferation assay revealed that RK15 was the most potent chalcone derivative in our library with IC 50 values of 3, 4, and 6 μM respectively in A375, A‐172, and HT‐29 cells. Interestingly, RK15 was much less potent in MCF7 cells, with an IC 50 of 85 μM. The second chalcone derivative, RK19, was much less potent than RK15, with IC 50 values ranging from 56 to 95 μM in these four cell lines. We investigated the mechanism of cell death elicited by these compounds using the Caspase‐Glo 3/7 assay. RK19 induced executioner caspase‐3/7 activity in A‐172, A375, and HT‐29 cells. An increase in caspase‐3/7 activity was also noted following RK15 treatment in A‐172 cells but interestingly not in HT‐29 cells. A reversal experiment using the pan‐caspase inhibitor Z‐VAD‐FMK was utilized to confirm the results from the Caspase‐Glo 3/7 assay. Since others have shown that chalcones can generate reactive oxygen species (ROS), we hypothesized that RK15 may lead to apoptosis through ROS generation. A DCFDA plate‐based assay was utilized to measure ROS generation following RK15 treatment. RK15 modestly increased ROS levels in A375 and HT‐29 cells, but not in A‐172 cells. These results suggest that though RK15 may increase ROS in some instances, an alternate mechanism of action is likely involved in the observed apoptotic effect.