Indomethacin and juglone inhibit inflammatory molecules to induce apoptosis in colon cancer cells

Abstract

Colorectal cancer (CRC) is the third most common fatal cancer. Indomethacin, a nonsteroidal anti-inflammatory drug, is known to reduce the occurrence of CRC.This study evaluated the potential anticolon cancer effects of juglone (5-hydroxy-1,4-naphthoquinone) in combination with indomethacin. Human colon adenocarcinoma cells (HT29) were subjected to treatment with indomethacin, juglone, and a combination of both. Morphological analysis, cell cycle regulation, and dual staining using acridine orange and ethidium bromide in control and treated cells revealed the apoptotic potential of these compounds. Bcl2 and inflammatory molecules (tumor necrosis factor-α, nuclear factor kappa B, and Cox-2) were found to be decreased with a concomitant increase in the expression of proapoptotic molecules (Bad, Bax, cytochrome c, and PUMA) as a result of the molecular regulation of Wnt, Notch, and peroxisome proliferator-activated receptor-γ signaling. Treatment with juglone was not as effective as with indomethacin; however, a combination of both was shown to be more effective, suggesting that juglone may be considered for therapeutic intervention of colon cancer.

α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors

“…The amplification of apoptosis and the overall antitumor effect of both COX-1 and COX-2 inhibitors have been repeatedly described for a variety of transformed cells. For example, a non-selective COX inhibitor used in this study, indomethacin, suppressed the growth of human colon adenocarcinoma cells [15], MNNG/HOS osteosarcoma cells [16], human H4 and U87 glioma cells [17], and many other cell lines. The proapoptotic effect of COX inhibitors is associated with both reduced COX catalytic activity and inhibition of PGE2 synthesis, even with COX-independent mechanisms [18,19].…”

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing

“…Recently, the potential antiproliferative effect in colorectal cancer of juglone in combination with indomethacin was investigated: the study showed superiority of the two-drug combination, whilst treatment with juglone alone was not as effective as with indomethacin [ 40 ].…”

“…When it comes to patients who have already developed colorectal cancer, data concerning clinical usefulness of NSAIDs are rarer; use of aspirin seems to improve survival particularly in patients with colorectal cancer harbouring PIK3CA mutations [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor

“…The mechanism of this process is due to increased levels of COX-2 and prostaglandin E2 (PGE 2 ) [4][5][6][7] that promote proliferation, migration, invasion, and cell adhesion [8,9]. According to these facts, medication with NSAIDs was associated with decreased risk of certain cancer types, particularly gastrointestinal tract cancers (gastric or colorectal cancer), lung, breast, and prostate cancers [10][11][12][13][14]. Clinical and pharmacoepidemiological studies provide evidence that aspirin and other cyclooxygenase-2 enzyme inhibitors lower recurrence of colorectal cancer by about 20% [12,15,16].…”