Diclofenac N-Derivatives as Therapeutic Agents with Anti-Inflammatory and Anti-Cancer Effect

Abstract

A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC50 values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC50 in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 µg·mL−1 concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC50 NO) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.

Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer

“…The overexpression of COX-2 in the bowel, accompanied by an elevation in prostaglandin E2, has been linked with chronic inflammatory conditions [ 8 ] and cancer [ 7 , 9 , 10 ]. Consistently, NSAIDs have been shown to display promising chemopreventive and antitumor properties, especially in colorectal cancer [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Efficient In Vitro and In Vivo Anti-Inflammatory Activity of a Diamine-PEGylated Oleanolic Acid Derivative

“…¾ IC 50 = 41.78 µg/mL, ½ IC 50 = 27.86 µg/mL, and ¼ IC 50 = 13.92 µg/mL for OA. These data for diclofenac were obtained from Galisteo et al 2020 [ 2 ]. The use of these sub-cytotoxic concentrations ensures that the anti-inflammatory activity is due to an inflammatory process and not to its cytotoxicity.…”

“…In recent years, new natural compounds with anti-inflammatory properties have been identified and studied, offering the potential to decrease excessive inflammation associated with many diseases [ 1 ]. Our research group has recently investigated the anti-inflammatory effect of various diclofenac derivatives [ 2 ].…”

NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future

“…Notably, a diclofenac Nderivative (VIII-4 in Figure 8) induced apoptosis and showed a better anti-inflammatory effect than its parent drug. 376…”