A small library of chalcone derivatives was synthesized and tested for anti‐proliferative activity in several human cancer cell lines (A375 melanoma, CRL‐1620 glioblastoma, HT‐29 colon carcinoma, and MCF‐7 breast adenocarcinoma). These novel chalcones (RK‐6 and RK‐7) incorporated privileged structures intended to quench glutathione or influence microtubule dynamics. We hypothesized that these compounds would decrease antioxidant capacity or disrupt cell division resulting in anti‐cancer effects. Each of the four cell lines was treated with 50 µM of RK‐6 or RK‐7 for 24 or 48 hours and relative cell numbers were measured using the CyQUANT® NF microplate assay according to the manufacturer's instructions. Treatment with RK‐6 and RK‐7 each resulted in a significant reduction in cell density and visual examination of cells following treatment revealed gross morphology suggestive of apoptosis. Additionally, we determined the GI50 for RK‐6 and RK‐7 in MCF‐7 cells by treating with increasing concentrations (1‐100 µM) of each compound separately for 48 hours, followed by the CyQUANT® NF assay. GI50 concentrations for RK‐6 and RK‐7 in MCF‐7 cells were 36 and 68 µM respectively. To determine whether these compounds were indeed cytotoxic, MCF‐7 cells were treated with RK‐6 or RK‐7 for 24 hours and then subjected to western blotting. RK‐6 but not RK‐7 caused cleavage of effector caspase‐7. Taken together, these results demonstrate that two novel chalcone derivatives possess anti‐cancer effects in multiple human cancer cell lines. Additional studies are underway to determine the mechanisms of anti‐cancer action of these compounds.
Since prostaglandins are critically involved in tumorigenesis, COX inhibitors, which reduce prostaglandins, have been investigated for anti‐cancer effects. We and others have shown that the COX‐2 selective inhibitor, celecoxib, induces apoptosis in various cancer cell lines. However, the role of COX inhibition in these anti‐cancer effects remains uncertain. Previously, we reported that celecoxib and another COX‐2 selective inhibitor, etodolac, increased COX‐2 protein levels in several human cancer cell lines (A375 melanoma, CRL‐1620 glioblastoma and HT‐29 colon carcinoma). A non‐selective inhibitor, ibuprofen, failed to increase COX‐2 expression in all but A375 cells. It is well known that COX‐2 is inducible by various stimuli. However, COX‐1 is constitutive and thought to be less dynamic. Here, COX‐1 levels were examined via western blotting to determine whether they were dynamic in response to treatment with various COX inhibitors. Celecoxib treatment for 24 hours induced COX‐1 in A375 cells. In contrast, COX‐1 levels were stable in celecoxib‐treated HT‐29 cells but were decreased in CRL‐1620 cells. COX‐1 levels were unaffected by etodolac treatment in all three cells lines. Ibuprofen treatment for 24 hours induced COX‐1 in A375 and CRL‐1620 cells, but not in HT‐29 cells. Meloxicam, another COX‐2 selective inhibitor, reduced COX‐1 levels but increased COX‐2 levels in CRL‐1620 cells. These results suggest that while COX‐1 is considered a constitutive enzyme, its levels can be modulated by COX inhibitors.
The COX‐2 selective inhibitor, celecoxib, causes cancer cell death in vitro. However, the mechanism(s) behind the observed cytotoxic effects are still being debated. We have demonstrated that celecoxib treatment induces caspase‐dependent apoptosis in several human tumor cell lines (A375 melanoma, HT‐29 colon carcinoma and CRL‐1620 glioblastoma). Given protective effects of certain prostaglandins, we hypothesized that the apoptotic effects of celecoxib may be in part due to COX‐2 inhibition. However, western blotting for COX‐2 in A375, HT‐29 and CRL‐1620 cells treated with celecoxib for 24 hours revealed a surprising result. Celecoxib induced COX‐2 levels in each of these lines in a dose‐dependent manner. To determine whether COX‐2 induction by celecoxib is a class effect, we included the COX‐2 selective inhibitor etodolac and the non‐selective COX inhibitor ibuprofen. Etodolac treatment for 24 hours induced COX‐2 in a dose‐dependent manner in A375 and CRL‐1620 cells and at the highest dose in HT‐29 cells. Treatment with ibuprofen for 24 hours induced COX‐2 in a dose‐dependent manner in only A375 melanoma cells. These results demonstrate that the COX‐2 inhibitors celecoxib and etodolac induce protein expression of COX‐2 in several human tumor cell lines, whereas induction by ibuprofen was only seen in A375 tumor cells. These data demonstrate that specific and non‐COX specific NSAIDs induce COX‐2 expression.
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