Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

Abstract

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1a,25 Dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) in regulating the growth and di erentiation of the normal prostate gland yet prostate cancer cells appear signi®cantly less sensitive to this action. Vitamin D 3 receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative e ects of 1a,25(OH) 2 D 3 and therefore it is unclear why prostate cancer cell lines are signi®cantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1a,25(OH) 2 D 3 are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 mM and 15 nM respectively), which alone were relatively inactive, synergized with 1a,25(OH) 2 D 3 in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D 3 hexa¯uoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclindependent kinase inhibitor, p21 (waf1/cip1) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1a,25(OH) 2 D 3 during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D 3 analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgendependent and independent prostate cancer. Oncogene (2001) 20, 1860 ± 1872.

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

“…Still, the given data obviously look only at a very small portion of possibly involved pathways and thus have to be considered as preliminary. It cannot be ruled out that the observed changes could be a parallel issue as for example growth inhibition, induced by sodium butyrate, has been described in a cell line that has abrogated Rb function (Rashid et al, 2001). There might be other and potentially even more important structures such as cyclin A and D, p27 and protein kinase C, which are involved in the process of butyrate-induced growth inhibition (Chen et al, 2003;Kim et al, 2003;Siddiqui et al, 2003).…”

“…There might be other and potentially even more important structures such as cyclin A and D, p27 and protein kinase C, which are involved in the process of butyrate-induced growth inhibition (Chen et al, 2003;Kim et al, 2003;Siddiqui et al, 2003). Nevertheless, exploring the activation of p-21, including the role of Sp1 transcription factor, is a very promising approach (Wang et al, 2000;Rashid et al, 2001;Margueron et al, 2003), as this gene appears to be rarely mutated in common human malignancies in contrast to p53 (Terao et al, 2001). A similar pattern of mechanism has been described for several cell lines including prostate cancer cell lines for the effect of phorbol ester (Blagosklonny et al, 1997).…”

“…In addition, cell culture experiments were carried out to gain a further insight into the pathways possibly influenced by butyrates. Based on previous reports, the induction of p21, activation of the Rb protein and expression of cmyc were evaluated under treatment conditions with the HDACs (Blagosklonny et al, 1997;Claassen and Hann, 2000;Rashid et al, 2001).…”

IFI16 in Human Prostate Cancer

“…Studies have indicated that treatment of human prostate cancer cell lines with inhibitors of HDACs suppresses cell growth (11,12). Moreover, studies have indicated that inhibitors of HDACs differentially induce apoptosis in prostate cancer cells (13,14).…”

Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1

“…They also block angiogenesis and stimulate immune system in vivo. 5,6 HDAC inhibitors have a selective toxicity against tumor cells and a synergistic activity with existing therapeutic agents, including retinoic acids, 7 vitamin D analogues 8 and peroxisome proliferator-activated receptor ligands. 9 A number of HDAC inhibitors are currently in phase I and II clinical trials (eg depsipeptide, AN-9: pivaloyloxymethyl butyrate), and encouraging results have been reported for their use in the treatment of both hematological malignancies and solid tumors.…”