Dietary feeding of flavokawain A, a Kava chalcone, exhibits a satisfactory safety profile and its association with enhancement of phase II enzymes in mice

Abstract

Flavokawain A (FKA), a major chalcone in the Kava plant, has recently demonstrated promising anti-cancer activities. A systematic evaluation of FKA's safety profile has not been reported before. In this study, male FVB/N mice were fed with an AIN-76A diet or AIN-76A diet supplemented with 0.6% (6 g/kg food) FKA or 0.6% commercial kava root extract (KRE) for three weeks. Dietary feeding of FKA did not affect food consumption and body weight. Histopathological examination of liver, kidney, colon, lung, heart, spleen, and thymus revealed no signs of FKA-induced toxicity. Biochemical serum analysis and histological examination confirmed normal organ function in FKA-treated mice. The cytotoxicity profile showed FKA had minimal side effects on bone marrow and small intestinal epithelial cells compared with Adriamycin. In addition, oral feeding of FKA increased activities of both glutathione S-transferase and quinone reductase in the liver, lung, prostate and bladder tissues of mice. In comparison, dietary feeding of 0.6% KRE increased liver/body weight ratio and decreased spleen, thymus, and testis/body weight ratios, as well as induced nodular proliferation in liver tissues. Therefore, dietary feeding FKA showed no adverse effects on major organ function and homeostasis in mice, suggesting the potential of FKA for chemoprevention study of human cancers.

Flavokawain A inhibits Cytochrome P450 in in vitro metabolic and inhibitory investigations

“…Therefore, kava extracts as beverage have been increasingly developed and used to prevent bladder cancer owing to its low toxicity (Li et al, 2014). However, there were reported cases of hepatotoxicity using commercial kava root extracts (Teschke, 2010;Teschke and Wolff, 2009).…”

Cancer preventive effects of a specific probiotic fermented milk containing Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2 on male F344 rats treated with 1,2-dimethylhydrazine

“…An enhancement of those enzymatic activities is considered to be beneficial for health since it means that the carcinogen excretion is also enhanced. This effect is correlated with a protection against chemically induced tumours as it is demonstrated in many studies (Li et al, 2014;Sangeetha, Viswanathan, Balasubramanian, & Nalini, 2012). For example, Vinothkumar et al (2014) showed that the supplementation of increasing doses of troxerutin ranging from 12.5 to 50 mg/kg was able to induce significantly (p < 0.05) the activities of phase II enzymes such as GST, DTD and UDPGD in DMH treated rats.…”

Induction of G2M Arrest by Flavokawain A, A Kava Chalcone, Increases the Responsiveness of HER2 Overexpressing Breast Cancer Cells to Herceptin

“…In addition, Herceptin plus FKA treatment led to enhanced inhibitory effects on the growth of HER2 overexpressing breast cancer cells. These results indicates that FKA with excellent safety profile [18,21] deserves further investigation for its potential use as an adjuvant agent in combination with Herceptin for treatment of HER2 positive breast cancer or as a preventative agent for targeting HER2 positive early breast cancer in preventing its recurrence and progression.…”

“…We have further demonstrated that FKA is a novel neddylation inhibitor and causes degradation of Skp2 protein [18,20]. Dietary feeding of FKA inhibits tumorigenesis in the mouse transgenic models of bladder and prostate carcinogenesis without exhibiting any adverse effects on major organ function (including liver function) and homoeostasis in mice [18,[20][21][22]. However, the effect of FKA on HER2 overexpressing breast cancer has not been reported yet.…”