Xanthohumol and structurally related prenylflavonoids for cancer chemoprevention and control

Abstract

Humans are almost exclusively exposed to the prenylated hop chalcone, xanthohumol, by consumption of beer and hop-derived dietary supplements. Its spontaneous isomerization into the flavanone, isoxanthohumol, in conjunction with gut microbial and hepatic metabolism, produces several xanthohumol-derived prenylated flavonoids that exert bioactivities relevant to cancer chemoprevention. The mechanisms by which these prenylflavonoids may act to counter tumorigenesis, as well as carcinogenesis and metastasis, include detoxifying carcinogens, reducing inflammation and inflammation-driven angiogenesis, and promoting apoptotic cell death. Following our discoveries that xanthohumol has the ability to inhibit cytochrome P450 enzymes that metabolically activate procarcinogens and induce the carcinogen-detoxifying quinone reductase, other researchers have investigated the effects of xanthohumol on the activity of these metabolic enzymes in various cancer cell lines using carcinogenic substrates as well as its effects on transcriptional activation of metabolic genes in animal models. Another group of metabolic enzymes, glutathione S-transferases, detoxify electrophilic carcinogens and appear to be transcriptionally induced by xanthohumol via activation of Nrf2. Various human malignancies have in common that they activate the pro-inflammatory NFκB pathway to induce the expression of inflammatory cytokines, growth factors, and anti-apoptotic genes. Many researchers, including our laboratory, have shown that xanthohumol and related flavonoids inhibit NFκB activation in various cancer cell lines. Furthermore, xanthohumol can inhibit tumor growth in vivo by inhibiting the pro-angiogenic NFκB and Akt pathways. Tumor cells differ from normal cells by their increased metabolic rate and demand for oxygen, which forces them to switch from oxidative phosphorylation to aerobic glycolysis to meet energy demands while coping with increased oxidative stress and apoptotic risk. Acting as mild mitochondrial uncouplers, prenylated flavonoids lower the mitochondrial inner membrane potential thereby promoting apoptosis, counteracting anti-apoptotic pathways in tumor cells, and decreasing the metastatic potential of cancer cells. While xanthohumol and other prenylated flavonoids have low potential for use as effective cancer therapeutics by themselves, they hold promise for combination therapy because tumor cells cannot develop resistance against the mitochondrial uncoupling effects of prenylated flavonoids.