Amentoflavone, a
biflavonoid from Selaginella tamariscina, is known to possess several bioactivities such as antitumor, anti-inflammatory, and antifungal effects. However, the mechanism of the anticancer effects of
amentoflavone on human
cervical cancer cells has not been studied in detail. In this study, we demonstrated that
amentoflavone induces apoptosis in SiHa and CaSki
cervical cancer cells by suppressing human papillomavirus
protein E7 expression. The
cyclins and
tumor suppressors were modulated by
amentoflavone in SiHa and CaSki human
cervical cancer cells:
cyclin and hyperphosphorylated
retinoblastoma (p-pRb) were down-regulated, whereas
cyclin-dependent kinase inhibitors and p53 were enhanced.
Amentoflavone up-regulated
peroxisome proliferator-activated receptor γ (PPARγ) and
phosphatase and
tensin homolog deleted on chromosome 10 (PTEN) expression levels while inhibiting E7-mediated
cyclooxygenase-2 (COX-2)/
interleukin-32 (IL-32) expressions were downregulated, and Akt phosphorlylation was decreased in an
amentoflavone-induced apoptotic process, suggesting that
amentoflavone may be a PPARγ activator. Additionally, the expression of the anti-apoptotic factor Bcl-2 was decreased, whereas that of the well-known apoptotic factor Bax was increased, thereby releasing
cytochrome c into cytosol in
amentoflavone-treated
cervical cancer cells. Furthermore,
amentoflavone treatment led to the activation of
caspase-3 and -9 and proteolytic cleavage of
poly(ADP-ribose) polymerase. The expression level of the extrinsic
death receptor Fas (CD95) was not altered by
amentoflavone treatment. When these findings are taken together, the
biflavonoid amentoflavone activates PPARγ/PTEN expressions and induces apoptosis via suppressing E7 expression, cell cycle arrest at sub-G₁ phase, and mitochondria-emanated intrinsic pathways in SiHa and CaSki human
cervical cancer cells. These findings suggest that
amentoflavone has potential for development as a therapeutic agent for human
cervical cancer.