5-Demethylnobiletin more potently inhibits colon cancer cell growth than nobiletin in vitro and in vivo

Abstract

Nobiletin (NOB) and 5-demethylnobiletin (DMNB) are unique polymethoxyflavones (PMFs) found in citrus peel that exhibit anti-tumoral action in several cancer cell models. The differences between NOB and DMNB with respect to their anti-proliferative potencies and underlying molecular mechanism were compared in this contribution. The results of the cell viability assay suggested that DMNB resulted in more enhanced growth inhibitory effects than NOB in human colon cancer cell lines (HCT-116, HT-29 and COLO 205). Flow cytometry data found that DMNB inhibited proliferation in COLO 205 cells by predominantly inducing apoptosis. A xenograft mouse model further demonstrated that DMNB exhibited more preferential anti-colon cancer effects than NOB via its ability to induce p53-regulated cell death signaling (apoptosis and autophagy) and inhibit key cellular markers associated with inflammation and angiogenesis. Taken together, our findings provide evidence for the first time that natural bioactive DMNB might serve as a promising polymethoxyflavone for chemoprevention of colorectal cancer.

Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention

“…In the following years, NOB and 5-DMN were also reported to be cytotoxic towards different colon cancer cell lines, including HCT116, HT-29, SW489, COLO320, COLO205 and Caco-2 (Table 1). Despite the stronger anti-proliferative effect of NOB observed in the earlier study [70], recent studies increasingly showed that 5-DMN exhibits stronger cytotoxic effects against different colon cancer cells as compared to NOB [49,63]. These contradictory results are potentially due to the different aspects of cancer focused in each study.…”

“…This flavone has a distinct three aromatic ring structure (labelled A, B and C in Figure 1), with the ketone and ether group in ring C along with four methoxy groups at the 5, 6, 7 and 8 positions of ring A and 2 methoxy groups at the 3 and 4 positions of ring B. Under long-term storage, NOB can degrade into 5-demethylnobiletin (5-DMN), IUPAC name 5-hydroxy- 6,7,8,3′,4′-pentamethoxyflavone (structure illustrated in Figure 1), through the process of autohydrolysis [49]. It has also been proposed that 5-DMN could be formed through conversion of nobiletin by gastric acid after oral consumption [50].…”

“…A recent study by Chiou et al also shows that the hydroxylated PMF, 5-DMN is more potent than NOB in terms of its chemopreventive effect on colon malignancy for both in vivo studies using xenograft mice and in vivo studies using three different colon cell lines. Chiou and colleagues reported that 5-DMN shows different levels of inhibition in different types of cell lines, with the highest efficacies in COLO205 cell lines, followed by HCT116 and HT-29 [49]. This is consistent with the findings of Qiu et al stating that the half maximal inhibitory concentration (IC 50 ) required for 5-DMN to exert an inhibitory effect on the growth of HCT116 cells is 8.4 μM as compared to the notably higher value of 37 μM for NOB.…”

“…Similarly, the IC 50 required for 5-DMN against HT-29 cells is 22 μM as compared to the higher IC 50 of 46.2 μM for NOB [63]. This may suggest that the hydroxyl group at the 5th position on the A ring is an important functional group involved in the molecular interactions [49].…”

“…Further support for NOB as a prospective candidate for chemoprevention is that NOB is known to inhibit different pathways leading to cancer via a number of different mechanisms which includes inhibiting cell cycle progression [54,76], limiting inflammation [76], inducing apoptosis [54], preventing angiogenesis [77] and reducing tumour formation [49,54,78]. This subsection will describe the mechanism of action of NOB, its autohydrolysis product, 5-DMN and its three common metabolites, namely 3′-DMN, 4′-DMN and 3′,4′-DMN, in chemoprevention of CRC in detail.…”