Flavokawain Research Articles

An in silico approach in predicting the possible mechanism involving restoration of wild-type p53 functions by small molecular weight compounds in tumor cells expressing R273H mutant p53.

R273H mutant p53 is a DNA-contact mutant that renders p53 dysfunctional due to a single substitution of Arg273 for His273. Rescuing R273 mutant p53 implies that a competent molecule would have to bind to the site of DNA-contact hot spots to complement the loss of contact with the DNA-binding domain. Here, curcumin, flavokawain B, and alpinetin were docked against the crystal structure of R273H mutant p53 in silico. Consequently, all the compounds bind to the cavity of R273H mutant p53 with a dissociation constant estimated to have 36.57, 70.77, and 75.11 µM for curcumin, flavokawain B, and alpinetin, respectively. Subsequently, each molecule was able to bind to the R273H mutant p53 by interacting with the DNA-contact hot spot Arg248 and mutant R273H, thereby compensating for the loss of direct contact with the DNA-binding domain. Furthermore, all the molecules were able to induce a direct contact with the consensus site of the DNA binding domain, thus maintaining DNA-contact residues with the DNA. The present findings offer preliminary indirect supporting evidence that small molecular weight compounds may certainly rescue DNA-contact mutant p53, which may lay a foundation for designing a competent and effective molecule capable of rescuing mutant p53 in tumor cells expressing R273H mutant p53.

Research on the effect of Flavokawain B on the proliferation and apoptosis of acute T lymphoblastic leukemia cells

Objective To explore the effect of Flavokawain B on the proliferation and apoptosis of acute T lymphoblastic leukemia(T-ALL) cells and its preliminary mechanism. Methods After the T-ALL cell lines CEM-C7(sensitive to glucocorticoids) and MOLT-4(resistant to glucocorticoids) cells were treated with different concentrations of Flavokawain B, the influence of Flavokawain B on the growth rate and doubling time of CEM-C7 and MOLT-4 cells was observed by 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) assay, and apoptosis was analyzed by using flow cytometry. Furthermore, Wes-tern blot assay was used to detect the expressions of Bim, Bcl-2 and cleaved Caspase-9. At last, the expressions of Bim and Bcl-2 in clinical T-ALL patient samples were also detected by using Western blot assay. Results MTS assay showed that Flavokawain B significantly inhibited the cellular proliferation of T-ALL cell lines in a dose and time dependent manner(P<0.01). Flow cytometry findings revealed that Flavokawain B significantly induced the apoptosis of T-ALL cells in a dose-dependent manner(P<0.001). Western blot results indicated that Flavokawain B increased the expression of Bim and cleaved Caspase-9, and decreased the expression of Bcl-2 in T-ALL cell lines, which increased Bim and decreased Bcl-2 in clinical T-ALL patients samples, both in a dose-dependent manner. Conclusions Flavokawain B can inhibit the proliferation and induce the apoptosis of T-ALL cells by up-regulating the expression of Bim and down-regulating the expression of Bcl-2 and activating Caspase-9, whether resistant to glucocorticoids or not. Key words: T lymphoblastic leukemia, acute; Flavokawain B; Proliferation; Apoptosis