Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice

Liu, Zhongbo; Song, Liankun; Xie, Jun; Simoneau, Anne R.; Uchio, Edward; Zi, Xiaolin

doi:10.3390/pharmaceutics14030496

Cited by 10 publications

(21 citation statements)

References 26 publications

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“…Therefore, CSCs have been considered as a driver for cancer initiation, progression, metastasis, drug resistance, and recurrence (3,14,16). We have demonstrated that FKA, a novel chalcone from the kava plant, inhibits the growth of bulk tumor cells in different transgenic models and xenograft tumor models (6)(7)(8)23). The bulk of tumors consists of heterogenous cell populations, including non-CSCs and CSCs.…”

Section: Discussionmentioning

confidence: 99%

Flavokawain A Reduces Tumor-Initiating Properties and Stemness of Prostate Cancer

et al. 2022

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We have previously demonstrated the in vivo chemopreventive efficacy of flavokawain A (FKA), a novel chalcone from the kava plant, in prostate carcinogenesis models. However, the mechanisms of the anticarcinogenic effects of FKA remain largely unknown. We evaluated the effect of FKA on prostate tumor spheroid formation by prostate cancer stem cells, which were sorted out from CD44+/CD133+ prostate cancer cells 22Rv1 and DU145. FKA treatment significantly decreased both the size and numbers of the tumor spheroids over different generations of spheroid passages. In addition, the dietary feeding of FKA-formulated food to Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice bearing CD44+/CD133+ 22Rv1 xenograft tumors resulted in a significant reduction of tumor growth compared to those fed with vehicle control food–fed mice. Furthermore, the expression of stem cell markers, such as Nanog, Oct4, and CD44, were markedly downregulated in both tumor spheroids and tumor tissues. We also observed that FKA inhibits Ubc12 neddylation, c-Myc, and keratin-8 expression in both CD44+/CD133+ prostate tumor spheroids and xenograft tumors. Our results suggest that FKA can reduce the tumor-initiating properties and stemness of prostate cancer, which provides a new mechanism for the chemoprevention efficacy of FKA.

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Section: Discussionmentioning

confidence: 99%

Flavokawain A Reduces Tumor-Initiating Properties and Stemness of Prostate Cancer

et al. 2022

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“…Zi et al recognized FKA as a major component in kava and showed that it had a major effect on inhibiting BC tumorigenesis (Figs. 3c) [30]. We tested the effective dose of three kava extracts, FKA, FKB, and FKC, and found that BC cells were most sensitive to FKA (Figs.…”

Section: Evaluation Of Fka As a Candidate Drug For Targeting Prmt5mentioning

confidence: 99%

“…In addition, FKA could induce a G2-M arrest in the bladder and prostate cancer cells [28,29]. In mouse models, FKA targeted the activated Ha-Ras pathway for the prevention and treatment of non-muscle invasive BC [30]. FKA is not metabolized by the liver, but is mainly concentrated in urine, indicating that orally administrated FKA could specifically act on urinary tract carcinoma [28].…”

Section: Introductionmentioning

confidence: 99%

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Liu

Piao

et al. 2022

J Exp Clin Cancer Res

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Background Protein arginine methyltransferases (PRMTs) regulate protein biological activity by modulating arginine methylation in cancer and are increasingly recognized as potential drug targets. Inhibitors targeting PRMTs are currently in the early phases of clinical trials and more candidate drugs are needed. Flavokawain A (FKA), extracted from kava plant, has been recognized as a potential chemotherapy drug in bladder cancer (BC), but its action mechanism remains unclear. Methods We first determined the role of a type II PRMT, PRMT5, in BC tissue samples and performed cytological experiments. We then utilized bioinformatics tools, including computational simulation, virtual screening, molecular docking, and energy analysis, to identify the potential use of PRMT5 inhibitors for BC treatment. In vitro and in vivo co-IP and mutation assays were performed to elucidate the molecular mechanism of PRMT5 inhibitor. Pharmacology experiments like bio-layer interferometry, CETSA, and pull-down assays were further used to provide direct evidence of the complex binding process. Results Among PRMTs, PRMT5 was identified as a therapeutic target for BC. PRMT5 expression in BC was correlated with poor prognosis and manipulating its expression could affect cancer cell growth. Through screening and extensive experimental validation, we recognized that a natural product, FKA, was a small new inhibitor molecule for PRMT5. We noticed that the product could inhibit the action of BC, in vitro and in vivo, by inhibiting PRMT5. We further demonstrated that FKA blocks the symmetric arginine dimethylation of histone H2A and H4 by binding to Y304 and F580 of PRMT5. Conclusions In summary, our research strongly suggests that PRMT5 is a potential epigenetic therapeutic target in bladder cancer, and that FKA can be used as a targeted inhibitor of PRMT5 for the treatment of bladder cancer.

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“…The male homozygous UPII-mutant Ha-ras transgenic model allows us to study the effect of an agent on the survival (one of the most important endpoints for cancer prevention and treatment) of bladder tumor-bearing mice in a feasible way. Molecularly, the UPII-mutant Ha-ras transgenic model mirrors high mTOR activity, which presents in approximately 70% of human urinary bladder cancer [ 6 , 7 , 8 , 9 ]. The mTOR pathway regulates aerobic glycolysis, and then rewires the metabolic programs of the tumor cells to promote cell proliferation [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…The mTOR pathway regulates aerobic glycolysis, and then rewires the metabolic programs of the tumor cells to promote cell proliferation [ 10 ]. Therefore, the male homozygous UPII-mutant Ha-ras transgenic model is currently the most suitable model for examining the preventive and treatment effects of novel agents on bladder cancer metabolism and recurrence progression [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism

et al. 2023

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UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (p = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (p = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells.

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Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice

Cited by 10 publications

References 26 publications

Flavokawain A Reduces Tumor-Initiating Properties and Stemness of Prostate Cancer

Flavokawain A Reduces Tumor-Initiating Properties and Stemness of Prostate Cancer

Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism

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