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. 2020 Sep 28;10(1):15904.
doi: 10.1038/s41598-020-73058-4.

Kava constituents exert selective anticancer effects in oral squamous cell carcinoma cells in vitro

Antonio Celentano  1 , Callisthenis Yiannis  2 , Rita Paolini  2 , Pangzhen Zhang  3 , Camile S Farah  4   5 , Nicola Cirillo  2 , Tami Yap  2 , Michael McCullough  2
Affiliations

Kava constituents exert selective anticancer effects in oral squamous cell carcinoma cells in vitro

Antonio Celentano et al. Sci Rep. .

Abstract

Kava is a beverage made from the ground roots of the plant Piper Methysticum. Active compounds of Kava have previously been demonstrated to exert an antiproliferative effect through cell cycle arrest and promotion of apoptosis. Our aim was to investigate the in vitro effects of the main constituents derived from Kava on oral squamous cell carcinoma (OSCC) activity. Gas chromatography mass spectrometry (GCMS) was used to characterise the main constituents of two Kava preparations. Cell proliferation was assessed in two human OSCC cell lines (H400 and BICR56) and in normal oral keratinocytes (OKF6) treated with the identified Kava constituents, namely Flavokawain A (FKA), Flavokawain B (FKB), yangonin, kavain and methysticin using an MTS in vitro assay. Cell migration at 16 h was assessed using a Transwell migration assay. Cell invasion was measured at 22 h using a Matrigel assay. Cell adhesion was assessed at 90 min with a Cytoselect Adhesion assay. The two Kava preparations contained substantially different concentrations of the main chemical constituents. Treatment of malignant and normal oral keratinocyte cell lines with three of the identified constituents, 10 μg/ml FKA, 2.5 μg/ml FKB and 10 μg/ml yangonin, showed a significant reduction in cell proliferation in both H400 and BICR56 cancer cell lines but not in normal OKF6 cells. Remarkably, the same Kava constituents induced a significant reduction of OSCC cell migration and invasion. We have demonstrated, for the first time, that Kava constituents, FKA, FKB and yangonin have potential anticancer effects on OSCC. This highlights an avenue for further research of Kava constituents in the development of future cancer therapies to prevent and treat OSCC.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Piper Methysticum specimens. Piper Methysticum pressed plant specimens from the collection of the National herbarium of Victoria collection. Images were captured with a Leaf Aptus‐II 10 Digital Back camera. Reproduced with permission from the Royal Botanic Gardens Victoria.
Figure 2
Figure 2
Chromatograms showing the differences in Kava constituents between two Kava samples. (A) Kava Fiji; (B) Kava Vanuatu. Peaks: (1) internal standard, methyl heptadecanoate; (2) dihydrokavain; (3) kavain; (4) desmethoxyyangonin; (5) dihydromethysticin; (6) flavokawain B; (7) yangonin; (8) methysticin; (9) flavokawain A. Flavokawain C not detected in either of the samples.
Figure 3
Figure 3
MTS assay. the effect of 2.5 μg/ml, 5 μg/ml and 10 μg/ml of FKA, FKB, yangonin, methysticin and kavain on OKF6 (A), H400 (B) and BICR56 (C) cell proliferation. Data are represented as mean ± SD. Statistical significance is given as follows: *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001; compared to control group.
Figure 4
Figure 4
Migration assays. migrated cell count of H400 and BICR56 cells incubated with 10 μg/ml FKA, 2.5 μg/ml FKB and 10 μg/mL yangonin. The results were representative of 3 independent experiments. The representative microscopic fields showed (digital white light microscopy, 460 × magnification) are H400 and BICR56 migrated cells at 16 h when treated with no treatment (control), 10 μg/ml FKA, 2.5 μg/ml, FKB and 10 μg/mL yangonin. Data are represented as mean ± SD. Statistical significance is given as follows: *p < 0.05; **p < 0.005; compared to control group.
Figure 5
Figure 5
Invasion assays. invaded cell count of H400 and BICR56 cells incubated with 10 μg/ml FKA, 2.5 μg/ml FKB and 10 μg/mL yangonin. Images were taken after 22 h at × 20 magnification (optical white light microscopy) showing fewer invading cells for treated groups compared to the control (representative fields). Graphs show quantification of invasion assays. The results were representative of 3 independent experiments. Data are represented as mean ± SD. Statistical significance is given as follows: *p < 0.05; compared to control group.
Figure 6
Figure 6
Adhesion assay. the effect of 10 μg/ml FKA, 2.5 μg/ml FKB and 10 μg/mL yangonin on H400 and BICR56 cells. Data are represented as mean ± SD. Statistical significance is given as follows: *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001; compared to control group.
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