Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice.
Consumption of the traditional kava preparation was reported to correlate with low and uncustomary gender ratios (more cancer in women than men) of cancer incidences in three kava-drinking countries: Fiji, Vanuatu, and Western Samoa. We have identified flavokawain A, B, and C but not the major kavalactone, kawain, in kava extracts as causing strong antiproliferative and apoptotic effect in human bladder cancer cells. Flavokawain A results in a significant loss of mitochondrial membrane potential and release of cytochrome c into the cytosol in an invasive bladder cancer cell line T24. These effects of flavokawain A are accompanied by a time-dependent decrease in Bcl-x(L), a decrease in the association of Bcl-x(L) to Bax, and an increase in the active form of Bax protein. Using the primary mouse embryo fibroblasts Bax knockout and wild-type cells as well as a Bax inhibitor peptide derived from the Bax-binding domain of Ku70, we showed that Bax protein was, at least in part, required for the apoptotic effect of flavokawain A. In addition, flavokawain A down-regulates the expression of X-linked inhibitor of apoptosis and survivin. Because both X-linked inhibitor of apoptosis and survivin are main factors for apoptosis resistance and are overexpressed in bladder tumors, our data suggest that flavokawain A may have a dual efficacy in induction of apoptosis preferentially in bladder tumors. Finally, the anticarcinogenic effect of flavokawain A was evident in its inhibitory growth of bladder tumor cells in a nude mice model (57% of inhibition) and in soft agar.
Zi
Xiaolin
X
Department of Urology and Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA. xzi@uci.edu
Simoneau
Anne R
AR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D020901:Kava / Q000737:chemistry*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009363:Neoplasm Proteins; D010936:Plant Extracts / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D000077022:Survivin; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C107489:BIRC5 protein, human; C494827:Bax protein, mouse; D005419:Flavonoids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010936:Plant Extracts; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; C500809:flavokawain A; C452039:flavokawain B; D002599:Chalcone; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases