Betulinic acid suppresses constitutive and TNFα‐induced NF‐κB activation and induces apoptosis in human prostate carcinoma PC‐3 cells

Abstract

Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-κB transcription factors that regulate several cell survival and antiapoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-κB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-κB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-κB/p65. BetA-mediated NF-κB inhibition involved decreased IKK activity and phosphorylation of IκBα at serine 32/36 followed by its degradation. Reporter assays revealed that NF-κB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFα-induced activation of NF-κB via the IκBα pathway, thereby sensitizing the cells to TNFα-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-κB activation and supports the rationale for targeting NF-κB through combination protocols with BetA in androgen-refractory prostate cancer.

Jamun (<i>Syzygium cumini </i>(L.)): A Review of Its Food and Medicinal Uses

“…Pronounced effects were when querecetin was administered before radiation [112,113] 3 Gallic acid 1) Inhibits radiation-induced damage to DNA and lipid peroxidation in both in vitro and in vivo conditions [114]. Inactivates phosphorylation of cdc25A/cdc25Ccdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells [138]; 5) Possess anti-proliferative, pro-apoptotic and anti-tumorigenic effects against human prostate cells DU145 and 22Rv1 in vitro and in nude mice [139]; 6) Synergizes with doxorubicin to suppress the growth of DU145 cells [136]; 7) Induces apoptosis through both caspase-dependent and -independent pathways in the in A375.S2 human melanoma cells [140]; 8) Possesses in vitro anticancer effects against the human prostate cancer cells [141] 6 Betulinic acid 1) Is effective against a variety of cancer types but relatively safe to the normal cells and tissue at equal concentrations [141]; 2) Induces potent effect on growth inhibition, G2/M cell cycle arrest and triggers apoptosis in the human gastric adenocarcinoma AGS cells in vitro, possibly by the down-regulation of Hiwi and its downstream target Cyclin B1 expression [142]; 3) Causes a dose dependent cytotoxic effect on the rhabdomyosarcoma cell line RMS by inducing apoptosis through the intrinsic mitochondrial pathway. It also decreased GLI1, GLI2, PTCH1, and IGF2 expression as well as hedgehog-response in vitro.…”

Betulinic acid protects againstN-nitrosodimethylamine-induced redox imbalance in testes of rats

“…This triterpene has also been found in other plants, including Aziziphus species, Syzygium species, Diospyros species and Orthosiphon stamineus [9][10][11][12]. BA possesses biological properties, including anti-inflammatory and apoptotic effects [13,14]. Some outstanding biological activities of BA include selective anticancer activity against metastatic over non-metastatic cancer cells, selectivity against cancerous cells over non-cancerous cells and exhibition of cytotoxicity against cancers that are resistant to conventional cancer drugs [15][16][17][18].…”

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“…It is likely that context dependency also plays a role with respect to nuclear factor kappa-B (NF-κB) modulation. While NF-κB is activated by betulinic acid (20 µM) in a variety of cancer cell lines resulting in induction of apoptosis [26], NF-κB inhibition is observed in chemoresistant androgen-refractory prostate cancer cells exhibiting constitutive Rel/NF-κB activation [27]. Similar effects of triterpenes on NF-κB related to inflammation have been observed and are discussed later.…”