Gene Expression Analysis Reveals the Concurrent Activation of Proapoptotic and Antioxidant-Defensive Mechanisms in Flavokawain B–Treated Cervical Cancer HeLa Cells

Abstract

Flavokawain B (FKB) is known to possess promising anticancer abilities. This is demonstrated in various cancer cell lines including HeLa cells. Cervical cancer is among the most widely diagnosed cancer among women today. Though FKB has been shown to be effective in treating cancer cells, the exact molecular mechanism is still unknown. This study is aimed at understanding the effects of FKB on HeLa cells using a microarray-based mRNA expression profiling and proteome profiling of stress-related proteins. The results of this study suggest that FKB induced cell death through p21-mediated cell cycle arrest and activation of p38. However, concurrent activation of antioxidant-related pathways and iron sequestration pathway followed by activation of ER-resident stress proteins clearly indicate that FKB failed to induce apoptosis in HeLa cells via oxidative stress. This effect implies that the protection of HeLa cells by FKB from H2O2–induced cell death is via neutralization of reactive oxygen species.

The protective effects of Kava (Piper Methysticum) constituents in cancers: A systematic review

“…A total of 21 studies, comprising 15 in vitro (including 2 in situ; 1 ex vivo), 1 in vivo, and 5 that assessed both models, examined the anticancer effects of FKB. Across these studies, there was unanimous agreement that FKB had antiproliferative ability with the majority of papers reporting induction of G2/M arrest . One paper suggested FKB induced G0/G1 arrest .…”

“…Fourteen papers reported cell cycle arrest by FKA, FKB and/or FKC, at G2/M or G1 . Cells accumulated in the G2/M phase undergo apoptosis through the Bax‐initiated mitochondrial pathway .…”

“…Many of kava's active compounds instigate apoptosis through DNA fragmentation and mitochondrial membrane permeability via upregulation of the mitochondrial apoptosis cascade and Fas‐mediated apoptosis of caspase 8 . FKA, FKB and FKC induce apoptosis via the intrinsic pathway, associating with an increase in cytochrome c release leading to activation of caspase 3, 7, 8 and 9 . Caspase activation has numerous effects; however, the main mechanisms highlighted include PARP cleavage, increased ROS production, and consequent inhibition of PI3K/Akt phosphorylation in keratinocytes, reducing tumorigenesis …”

“…Kava has been of interest for its established anxiolytic effects. 55,56 However, there is now a growing recognition of its potential anti- 19,20,25,27,29,32,40,41,49,50,52,54 Caspase activation has numerous effects; however, the main mechanisms highlighted include PARP cleavage, increased ROS production, and consequent inhibition of PI3K/Akt phosphorylation in keratinocytes, reducing tumorigenesis. 20,21,25,29,32,40,49,50 In addition to increased caspase activation, FKA and FKB were associated with increased expression of pro-apoptotic proteins and decreased expression of anti-apoptotic proteins.…”

“…Across these studies, there was unanimous agreement that FKB had antiproliferative ability with the majority of papers reporting induction of G2/M arrest. 16,20,21,23,25,27,29,32,[51][52][53] One paper suggested FKB induced G0/G1 arrest. 35 Additionally, there was a general consensus that FKB induced apoptosis.…”