Pao Pereira Extract Suppresses Castration-Resistant Prostate Cancer Cell Growth, Survival, and Invasion Through Inhibition of NFκB Signaling

Abstract

Pao extract, derived from bark of Amazonian tree Pao Pereira, is commonly used in South American medicine. A recent study showed that Pao extract repressed androgen-dependent LNCaP prostate cancer cell growth. We hypothesize that Pao extract asserts its anticancer effects on metastatic castration-resistant prostate cancer (CRPC) cells. Pao extract suppressed CRPC PC3 cell growth in a dose-and time-dependent manner, through induction of apoptosis and cell cycle arrest. Pao extract treatment induced cell cycle inhibitors, p21 and p27, and repressed PCNA, Cyclin A and Cyclin D1. Furthermore, Pao extract also induced the upregulation of pro-apoptotic Bax, reduction of anti-apoptotic Bcl-2, Bcl-x L , and XIAP expression, which were associated with the cleavage of PARP protein. Moreover, Pao extract treatment blocked PC3 cell migration and invasion. Mechanistically, Pao extract suppressed phosphorylation levels of AKT and NFκB/p65, NFκB DNA binding activity, and luciferase reporter activity. Pao inhibited TNFα-induced relocation of NFκB/p65 to the nucleus, NFκB/p65 transcription activity, and MMP9 activity as shown by zymography. Consistently, NFκB/p65 downstream targets involved in proliferation (Cyclin D1), survival (Bcl-2, Bcl-x L , and XIAP), and metastasis (VEGFa, MMP9, and GROα/CXCL1) were also downregulated by Pao extract. Finally, forced expression of NFκB/p65 reversed the growth inhibitory effect of Pao extract. Overall, Pao extract induced cell growth arrest, apoptosis, partially through inhibiting NFκB activation in prostate cancer cells. These data suggest that Pao extract may be beneficial for protection against CRPC.

Pao Pereira Extract Attenuates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by inhibiting 5α-Reductase

“…Pao extract, derived from bark of Amazonian tree Pao Pereira, is commonly used in South American medicine to treat a variety of ailments including cancer 23,24 . We and others have reported that Pao extract can inhibit human prostate cancer cell proliferation and survival in vitro and in vivo 25,26 . However, there is no evidence on its effects on BPH.…”

“…The bark of Pao pereira shows anti-plasmodial, antinociceptive and anti-inflammatory activities 23,24 . Recent studies revealed that a β-carboline alkaloid-enriched Pao extract has inhibitory effects on two prostate cancer lines, LNCaP and PC3 by inhibiting cell proliferation and survival 25,26 . Moreover, Pao extract can also chemosensitize ovarian cancer cells to carboplatin and pancreatic cancer cells to gemcitabine, respectively 27–29 .…”

Extract of the Medicinal Plant Pao Pereira Inhibits Pancreatic Cancer Stem-Like Cell In Vitro and In Vivo

“…The extract of the bark of Pao Pereira (Pao) has long been used in complementary and alternative medicine on cancer patients, and has been reported recently to have tumor inhibitory effect toward prostate, ovarian and pancreatic cancers. 20 , 24 - 26 We previously reported that Pao induced pancreatic cancer cells apoptosis, and inhibited pancreatic tumor growth in mice. 25 The combination of Pao and gemcitabine showed synergistic antitumor effects.…”

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

“…Once the stimuli exist, cytosolic-localized NFκB complex is released from the tether of NFκB inhibitor α (IκBα) protein and translocates into nucleus, where it binds to its cognate DNA motif and transcriptionally regulates the downstream targets including Bcl2, cyclin D1, vimentin, MMP9, and VEGFa. 8 , 9 NFκB plays important roles in various cellular processes, including survival, inflammation, and angiogenesis. 10 , 11 Therefore, dysregulation of NFκB signaling pathway has been implicated in both cancer development and chemoresistance.…”