Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells

Abstract

Constitutively active mitogenic and pro-survival signaling cascades due to aberrant expression and interaction of growth factors and their receptors are well documented in human prostate cancer (PCa). EGF and IGF-1 are potent mitogens that regulate proliferation and survival of PCa cells via autocrine and paracrine loops involving both MAPK- and Akt-mediated signaling. Accordingly, here we assessed the effect of inositol hexaphosphate (IP6) on constitutive and ligand (EGF and IGF-1)-induced biological responses and associated signaling cascades in advanced and androgen-independent human PCa PC-3 cells. Treatment of PC-3 cells with 2 mM IP6 strongly inhibited both growth and proliferation and decreased cell viability; similar effects were also observed in other human PCa DU145 and LNCaP cells. IP6 also caused a strong apoptotic death of PC-3 cells together with caspase 3 and PARP cleavage. Mechanistic studies showed that biological effects of IP6 were associated with inhibition of both constitutive and ligand-induced Akt phosphorylation together with a decrease in total Akt levels, but a differential inhibitory effect on MAPKs ERK1/2, JNK1/2 and p38 under constitutive and ligand-activated conditions. Under similar condition, IP6 also inhibited AP-1 DNA binding activity and decreased nuclear levels of both phospho and total c-Fos and c-Jun. Together, these findings for the first time establish IP6 efficacy in inhibiting aberrant EGFR or IGF-1R pathway-mediated sustained growth promoting and survival signaling cascades in advanced and androgen-independent human PCa PC-3 cells, which might have translational implications in advanced human PCa control and management.

Energy deprivation by silibinin in colorectal cancer cells

“…At 60% confluency, cells were serum starved (SS) for 24 h, treated with 100 μM silibinin and after 2 h, stimulated with EGF or IGF1 (50 ng/mL), and harvested as described previously. 47 In experiments, using inhibitors like antioxidants, PD98059, and 3MA, cells were pretreated with inhibitors for 2 h followed by silibinin treatment. For autophagic flux determination, lysosomal inhibitors: E64d and pepstatin A were added to the media with silibinin and incubated for respective time periods.…”

“…Trypan blue dye-exclusion and/or MTT assay was used to assess cell viability. 47 For in vitro clonal analysis, single cells were plated at a density of 1000 cells/well in a six well plate and cultured for 1 week in media under serum conditions with or without silibinin, which was then replenished after every 72 h. Number of cells/ individual clones was counted at experiment end, and clones cells display redox vulnerability which on exposure to silibinin causes them to generate more oxidative stress so as to compromise cellular viability. We do realize that more mechanistic studies need to be performed in the future to determine the mechanism associated with the differential response of CRC cells and normal colon cells to silibinin.…”

Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease

“…Both myo-Ins and InsP 6 have been also proven to be effective as safe chemopreventive agents, by triggering anti-oxidant and anti-inflammatory effects [93]. Namely, it has been demonstrated that InsP 6 inhibits IGF-1 receptor (IGF-1R) pathway-mediated sustained growth in cancer [94]. Given that myo-Ins may efficiently counteract insulin resistance (IR), it is tempting to speculate that it may also prevent IGF-1 increase associated to IR.…”

Differential Effect of Grape Seed Extract against Human Non-small-Cell Lung Cancer Cells: The Role of Reactive Oxygen Species and Apoptosis Induction

“…ERK1/2 is a survival moderator, however sustained ERK1/2 activation might also induce cell death [11]. The activation of JNK1/2 and p38 are generally implicated in the induction of cell death and inflammation after exposure to stress conditions [15]. MAPKs are also known to mediate apoptosis via activation of caspases [16].…”