Antiproliferative and Cytotoxic Activity of Xanthohumol and Its Non-Estrogenic Derivatives in Colon and Hepatocellular Carcinoma Cell Lines

Abstract

Xanthohumol (XN), a prenylated flavonoid found in hops, inhibits growth in a variety of cancer cell lines; however, its use raises concerns as gut microbiota and the host’s hepatic cytochrome P450 enzymes metabolize it into the most potent phytoestrogen known, 8-prenylnaringenin (8-PN). The XN derivatives dihydroxanthohumol (DXN) and tetrahydroxanthohumol (TXN) are not metabolized into 8-PN and they show higher tissue concentrations in vivo compared with XN when orally administered to mice at the same dose. Here we show that DXN and TXN possess improved anti-proliferative activity compared with XN in two colon (HCT116, HT29) and two hepatocellular (HepG2, Huh7) carcinoma cell lines, as indicated by their respective IC50 values. Furthermore, XN, DXN, and TXN induce extensive apoptosis in all these carcinoma cell lines. Finally, TXN induces G0/G1 cell cycle arrest in the colon carcinoma cell line HT29. Our findings suggest that DXN and TXN could show promise as therapeutic agents against colorectal and liver cancer in preclinical studies without the drawback of metabolism into a phytoestrogen.

Xanthohumol, a Prenylated Flavonoid from Hops, Induces DNA Damages in Colorectal Cancer Cells and Sensitizes SW480 Cells to the SN38 Chemotherapeutic Agent

“…We confirmed the results previously obtained by Liu et al, showing a depletion of cyclin B1 in HT29 [47], and by Logan et al, showing an arrest in the G0/G1 phase [48]. The differing results from these two authors probably result from the different concentrations used on this same HT29 line [47,48]. Here, we show that nontoxic concentrations of Xn (2.5-10 µM) were able to decrease key cyclins, such as cyclins A and B, and conversely to increase cyclin E, which controls checkpoint G1/S transition when associated with its cyclin-dependent kinases Cdk1 and 2, both of which are greatly increased depending on treatment time and concentrations (Figures 3 and 4).…”

“…The two most Xn-sensitive colon cancer cells, SW620 and HT29, both show disruption of the cell cycle in the G0/G1 and S phase, as revealed by analyzing cell distribution in phases and the key regulators of cell cycle, which are cyclins and their kinases, Cdks. We confirmed the results previously obtained by Liu et al, showing a depletion of cyclin B1 in HT29 [47], and by Logan et al, showing an arrest in the G0/G1 phase [48]. The differing results from these two authors probably result from the different concentrations used on this same HT29 line [47,48].…”

Xanthohumol, a Prenylated Flavonoid from Hops, Induces Caspase-Dependent Degradation of Oncoprotein BCR-ABL in K562 Cells

“…XN treatment also induced remarkable caspase activation in other types of cancer, such as gastric cancer [36] and thyroid cancer [20]. This was similar with the XN derivatives dihydroxanthohumol (DXN) and tetrahydroxanthohumol (TXN), which possess improved anti-proliferative activity compared with XN and could also induce obvious caspase-mediated apoptosis [47]. Finally, using the autophagy inhibitor CQ, which could inhibit the autophagy and enhance the caspase activity [30], we found CQ enhanced XN-stimulated caspase activation and apoptosis (Figure 6c).…”

Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid

“…Colorectal carcinoma is the second leading cause of cancer-related deaths in the world and the third most common cause of cancer-related death in the United States [18,19]. Therefore, it is indispensable to discover new compounds for its prevention and treatment [20]. Literature reports have shown the antitumor activity of acridine and thiophene compounds against colorectal carcinoma cells [6,21].…”