Evidence for activation of mutated p53 by apigenin in human pancreatic cancer

Abstract

Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by Cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted

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

“…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. King et al (2012) also found that apigenin suppressed orthotopic pancreatic tumour growth in nude mice fed with a diet supplemented with 0.2% apigenin (w/w). Apigenin fed mice had remarkably elevated levels of apigenin detected in both plasma and pancreas, and no significant degradation of apigenin was detected even over 72 hours.…”

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

“…Specific to PDAC, TP53 gene mutations occur in more than 75% of patients and are shown to contribute to proliferation and even drive metastasis through gain of function activities (Iacobuzio-Donahue and Herman, 2014; Weissmueller et al, 2014). Previous studies have shown that exogenous delivery of p53 sensitizes PDAC to chemotherapy (Camp et al, 2013), treatment with adenovirus encoding p53 sensitizes PDAC to radiation (Li et al, 2013), and the use of small molecules like apigenin (King et al, 2012) or mouse double minute 2 homolog (MDM2) inhibitors (Azmi et al, 2010) can restore endogenous p53 function and slow PDAC proliferation. Although VSV encoding p53 has never been studied in PDAC cells, VSV-driven murine p53 gene expression resulted in enhanced antitumor activities in vivo against mammary adenocarcinoma (Heiber and Barber, 2011).…”

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…Another study demonstrates that apigenin induces apoptosis via downregulation of NF-κB, Akt and Bcl-2 and that mice show lower tumour volume after dietary apigenin treatment [7,84]. Kaempferol inhibits cell growth and induces apoptosis in pancreatic cancer cell lines [7,85].…”