Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and Ku70–Bax interaction in prostate cancer

Abstract

Dysfunction of the apoptotic pathway in prostate cancer cells confers apoptosis resistance towards various therapies. A novel strategy to overcome resistance is to directly target the apoptotic pathway in cancer cells. Apigenin, an anticancer agent, selectively toxic to cancer cells induces cell cycle arrest and apoptosis through mechanisms which are not fully explored. In the present study we provide novel insight into the mechanisms of apoptosis induction by apigenin. Treatment of androgen-refractory human prostate cancer PC-3 and DU145 cells with apigenin resulted in dose-dependent suppression of XIAP, c-IAP1, c-IAP2 and survivin protein levels. Apigenin treatment resulted in significant decrease in cell viability and apoptosis induction with the increase of cytochrome C in time-dependent manner. These effects of apigenin were accompanied by decrease in Bcl-xL and Bcl-2 and increase in the active form of Bax protein. The apigenin-mediated increase in Bax was due to dissociation of Bax from Ku70 which is essential for apoptotic activity of Bax. Apigenin treatment resulted in the inhibition of class I histone deacetylases and HDAC1 protein expression, thereby increasing the acetylation of Ku70 and the dissociation of Bax resulting in apoptosis of cancer cells. Furthermore, apigenin significantly reduced HDAC1 occupancy at the XIAP promoter, suggesting that histone deacetylation might be critical for XIAP downregulation. These results suggest that apigenin targets inhibitor of apoptosis proteins and Ku70–Bax interaction in the induction of apoptosis in prostate cancer cells and in athymic nude mouse xenograft model endorsing its in vivo efficacy.

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…This treatment induced apoptosis through downregulation of Bcl-2, upregulation of Apaf-1, p21/Waf1 and p53 expression, and inhibition of PI3K/Akt and NF-κB signaling pathways [136]. Shukla et al [137] demonstrated the ability of apigenin in inhibiting the IAP family of proteins, thereby making prostate cancer cells more susceptible to Bax-mediated apoptosis. Apigenin treatment to prostate cancer cells caused decrease in HDAC1 thereby altering acetylation status, resulting in increased acetylation of the lysine residues of Ku70, thereby releasing Bax from the complex facilitating apoptosis [137].…”

“…Shukla et al [137] demonstrated the ability of apigenin in inhibiting the IAP family of proteins, thereby making prostate cancer cells more susceptible to Bax-mediated apoptosis. Apigenin treatment to prostate cancer cells caused decrease in HDAC1 thereby altering acetylation status, resulting in increased acetylation of the lysine residues of Ku70, thereby releasing Bax from the complex facilitating apoptosis [137]. In further studies of apigenin-mediated apoptosis in prostate cancer cells, Sharma et al [138] demonstrate preferential uptake and accumulation of apigenin in the nuclear matrix, binding it with the DNA to reduce oxidative DNA damage and apoptosis in prostate epithelial cells.…”

Natural plant flavonoid apigenin directly disrupts Hsp90/Cdc37 complex and inhibits pancreatic cancer cell growth and migration

“…However, numerous in vivo studies revealed that apigenin showed ideal bioactivities in animal models given oral administration. Shukla, Fu, and Gupta (2014) reported that apigenin inhibited human prostate cancer cell line PC-3 proliferation with 40 µM IC50 value in vitro and suppressed prostate tumour growth in PC-3-derived xenograft nude mice model given 50 µg/mouse apigenin oral administration every day, whose doses are comparable to the daily consumption of flavonoid in humans. Wu et al (2014) proved that apigenin (30 mg/kg) oral administration inhibited pancreatic cancer tumour growth in xenograft nude mice model implanted with human pancreatic cancer cell line AsPc-1, on which apigenin showed anti-proliferative effect with an IC50 value of 28.5 µM in vitro.…”

Chloride Intracellular Channel 1 Regulates Prostate Cancer Cell Proliferation and Migration Through the MAPK/ERK Pathway

“…Localized prostate cancer is eminently treatable; however, no curative therapy is available once the cancer becomes invasive and metastasizes. 3,4 Therefore, identifying the role of new molecules of diagnostic and therapeutic significance remains a major focus of current cancer research.…”