Kava chalcone, flavokawain A, inhibits urothelial tumorigenesis in the UPII-SV40T transgenic mouse model
Zhongbo Liu1, Xia Xu, Xuesen Li
1Department of Urology, University of California, Irvine, 101 The City Drive South, Rt. 81 Bldg. 55 Rm. 302, Orange, CA 92868. xzi@uci.edu.
Abstract:
Flavokawain A (FKA) is the predominant chalcone identified from the kava plant. We have previously shown that FKA preferentially inhibits the growth of p53 defective bladder cancer cell lines. Here, we examined whether FKA could inhibit bladder cancer development and progression in vivo in the UPII-SV40T transgenic model that resembles human urothelial cell carcinoma (UCC) with defects in the p53 and the retinoblastoma (Rb) protein pathways. Genotyped UPII-SV40T mice were fed orally with vehicle control (AIN-93M) or FKA (6 g/kg food; 0.6%) for 318 days starting at 28 days of age. More than 64% of the male mice fed with FKA-containing food survived beyond 318 days of age, whereas only about 38% of the male mice fed with vehicle control food survived to that age (P = 0.0383). The mean bladder weights of surviving male transgenic mice with the control diet versus the FKA diet were 234.6 ± 72.5 versus 96.1 ± 69.4 mg (P = 0.0002). FKA was excreted primarily through the urinary tract and concentrated in the urine up to 8.4 μmol/L, averaging about 38 times (males) and 15 times (females) more concentrated than in the plasma (P = 0.0001). FKA treatment inhibited the occurrence of high-grade papillary UCC, a precursor to invasive urothelial cancer, by 42.1%. A decreased expression of Ki67, survivin, and X-linked inhibitor of apoptotic proteins (XIAP) and increased expression of p27 and DR5, and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive apoptotic cells were observed in the urothelial tissue of FKA-fed mice. These results suggest a potential of FKA in preventing the recurrence and progression of non-muscle-invasive UCC.
Insights
Flavokawain A (FKA) from kava shows promise in preventing bladder cancer progression. FKA-treated mice had improved survival, reduced tumor size, and inhibited high-grade urothelial cell carcinoma (UCC).
Area of Science:
- Oncology
- Natural Products Chemistry
- Cancer Prevention
Background:
- Flavokawain A (FKA), a chalcone from kava, selectively inhibits p53-deficient cancer cells.
- Human urothelial cell carcinoma (UCC) often involves defects in p53 and retinoblastoma (Rb) pathways.
- The UPII-SV40T transgenic mouse model mimics human UCC with these genetic defects.
Purpose of the Study:
- To investigate the efficacy of Flavokawain A (FKA) in preventing bladder cancer development and progression in vivo.
- To assess FKA's impact on survival, tumor growth, and molecular markers in a relevant preclinical model of urothelial cell carcinoma (UCC).
Main Methods:
- UPII-SV40T transgenic mice were fed either a control diet or a diet containing FKA (0.6%) for 318 days.
- Survival rates, bladder weights, and FKA concentration in plasma and urine were measured.
- Tumor incidence, grade, and expression of key proteins (Ki67, survivin, XIAP, p27, DR5) and apoptosis (TUNEL) were analyzed.
Main Results:
- FKA significantly increased survival in male mice (64% vs 38%) and reduced mean bladder weight (96.1g vs 234.6g).
- FKA concentrated in urine (up to 8.4 μmol/L) and inhibited high-grade papillary UCC by 42.1%.
- FKA treatment led to decreased expression of proliferation/survival markers (Ki67, survivin, XIAP) and increased apoptosis (TUNEL) and cell cycle inhibitors (p27, DR5).
Conclusions:
- Flavokawain A demonstrates significant potential in preventing the development and progression of non-muscle-invasive urothelial cell carcinoma (UCC).
- FKA's anti-cancer effects are mediated through reduced proliferation, increased apoptosis, and modulation of key signaling pathways.
- Urinary concentration of FKA suggests targeted delivery for bladder cancer prevention and treatment.
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