Enhanced killing of androgen-independent prostate cancer cells using inositol hexakisphosphate in combination with proteasome inhibitors

Abstract

Effective treatments for androgen-independent prostate cancer (AIPCa) are lacking. To address this, emerging therapeutics such as proteasome inhibitors are currently undergoing clinical trials. Inositol hexakisphosphate (IP6) is an orally non-toxic phytochemical that exhibits antitumour activity against several types of cancer including PCa. We have previously shown that treatment of PC3 cells with IP6 induces the transcription of a subset of nuclear factor-kB (NF-kB)-responsive and pro-apoptotic BCL-2 family genes. In this study, we report that although NF-kB subunits p50/p65 translocate to the nucleus of PC3 cells in response to IP6, inhibition of NF-kBmediated transcription using non-degradable inhibitor of kB (IkB)-a does not modulate IP6 sensitivity. Treatment with IP6 also leads to increased protein levels of PUMA, BIK/NBK and NOXA between 4 and 8 h of treatment and decreased levels of MCL-1 and BCL-2 after 24 h. Although blocking transcription using actinomycin D does not modulate PC3 cell sensitivity to IP6, inhibition of protein translation using cycloheximide has a significant protective effect. In contrast, blocking proteasome-mediated protein degradation using MG-132 significantly enhances the ability of IP6 to reduce cellular metabolic activity in both PC3 and DU145 AIPCa cell lines. This effect of combined treatment on mitochondrial depolarisation is particularly striking and is also reproduced by another proteasome inhibitor (ALLN). The enhanced effect of combined MG132/IP6 treatment is almost completely inhibited by cycloheximide and correlates with changes in BCL-2 family protein levels. Altogether these results suggest a role for BCL-2 family proteins in mediating the combined effect of IP6 and proteasome inhibitors and warrant further pre-clinical studies for the treatment of AIPCa.

BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes

“…Treatment with DNMT1 inhibitors and HDAC inhibitors which activate Bik expression from the endogenous (silenced) Bik locus and the use of proteasomal inhibitors that stabilize BIK protein (in addition to other BH3-only members such as BIM and NOXA) appear to be highly promising anticancer approaches. The efficacy of proteasome inhibitors was also reported to be enhanced in combination with other chemotherapeutic agents such as TRAIL (Nikrad et al, 2005; Zhu et al, 2005a), cisplatin (Li et al, 2008) and inositol hexakisphosphate (Diallo et al, 2008). …”

MG132, a proteasome inhibitor, attenuates pressure-overload-induced cardiac hypertrophy in rats by modulation of mitogen-activated protein kinase signals

“…It has been reported that pharmacological inhibition of the proteasome was associated with alterations in protein expression profile of cardiomyocyte, and modulated cardiovascular disease progression [12,13]. MG132, a specific proteasome inhibitor, has been shown to suppress proliferation and inflammation [14], and possess proapoptotic [15,16] and antineoplastic [17,18] activities.…”

Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate

“…Thereby the question is still open and further studies are warranted to understand whether p53 activity is effectively required in mediating anticancer effects displayed by both InsP6 and myo-Ins. Downstream of p53 InsP6 has been demonstrated to reduce prosurvival factors and to upregulate caspases and other components of the proapoptotic BCL-2 family [ 63 – 66 ]. Furthermore, InsP6 has been shown to inhibit NF-kB activity in different cancers [ 67 , 68 ].…”