Altholactone Inhibits NF-κB and STAT3 Activation and Induces Reactive Oxygen Species-Mediated Apoptosis in Prostate Cancer DU145 Cells

Abstract

Altholactone, a natural compound isolated from Goniothalamus spp., has demonstrated anti-inflammatory and anticancer activities, but its molecular mechanisms are still not fully defined. Nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play pivotal roles in the cell survival of many human tumors. The objective of this study was to elucidate the mechanism of action of altholactone against prostate cancer DU145 cells and to evaluate whether its effects are mediated by inhibition of NF-κB and STAT3 activity. Altholactone inhibited proliferation of DU145 cells and induced cell cycle arrest in S phase and triggered apoptosis. Reporter assays revealed that altholactone repressed p65- and TNF-α-enhanced NF-κB transcriptional activity and also inhibited both constitutive and IL-6-induced transcriptional activity of STAT3. Consistent with this, altholactone down-regulated phosphorylation of STAT3 and moreover, decreased constitutively active mutant of STAT3 (STAT3C)-induced transcriptional activity. Altholactone treatment also results in down-regulation of STAT3 target genes such as survivin, and Bcl-2 followed by up regulation of pro-apoptotic Bax protein. However, pre-treatment with the antioxidant N-acetylcysteine (NAC) significantly inhibited the activation of Bax and prevented down-regulation of STAT3 target genes. Collectively, our findings suggest that altholactone induces DU145 cells death through inhibition of NF-κB and STAT3 activity.

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“…In this work, a known compound altholactone was isolated from the plant Polyalthia sp. Altholactone has demonstrated anti-inflammatory and anticancer activities against eukaryotic tumor cells, and antifungal/antimicrobrial activity against both gram positive and negative bacteria [32][33][34][35], but the molecular mechanisms responsible were still not fully defined. Studies have also shown altholactone cytotoxicity against human HeLa cells with an IC 50 of 148.7 µM [23].…”

“…Studies have also shown altholactone cytotoxicity against human HeLa cells with an IC 50 of 148.7 µM [23]. Mechanism studies reported that altholactone inhibited the growth of human bladder cancer T24 cells (IC 50 = 43.5 µM) by inducing apoptosis [35] and induced DU145 cell death (IC 50 = 38.5 µM), through inhibition of NF-κB and STAT3 activity [34].…”

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“…Numerous preclinical studies indicate that the treatment resistance is also resulted from the cancer related activation of nuclear factor kappa B (NF-κB) [ 83 ]. Therefore, selected inhibitors of NF-κB and signal transducer and activator of transcription 3 (STAT3) signaling pathways have been tested to increase the effectiveness of treatment of metastatic prostate cancer [ 26 , 84 ]. Notably, EC-70124 (glycosylated indolocarbazole multikinase inhibitor) had profound effects on the prostate cancer stem cell (CSC) subpopulation both in vitro and in vivo.…”

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