Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Abstract

Bisphosphonates are widely used agents for the treatment of malignant bone disease. They inhibit osteoclastmediated bone resorption and can have direct effects on cancer cells. In this study, we investigated whether the anticancer activity of the third-generation bisphosphonate zoledronic acid (ZOL) could be enhanced by combination with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). We found that ZOL and SAHA cooperated to induce cell death in the prostate cancer cell lines LNCaP and PC-3. The effect was synergistic, as evidenced by combination index isobologram analysis. ZOL and SAHA synergized to induce dissipation of the mitochondrial transmembrane potential, to activate caspase-3, and to trigger DNA fragmentation, showing that the combination of ZOL and SAHA resulted in the initiation of apoptosis. Because ZOL acts by inhibiting the mevalonate pathway, thereby preventing protein prenylation, we explored whether the mevalonate pathway was also the target of the cooperative action of ZOL and SAHA. We found that geranylgeraniol, but not farnesol, significantly reduced ZOL/SAHA-induced cell death, indicating that the synergistic action of the agents was due to the inhibition of geranylgeranylation. Consistently, a direct inhibitor of geranylgeranylation, GGTI-298, synergized with SAHA to induce cell death, whereas an inhibitor of farnesylation, FTI-277, had no effect. In addition, SAHA synergized with mevastatin, an inhibitor of the proximal enzyme in the mevalonate pathway. These in vitro findings provide a rationale for an in vivo exploration into the potential of combining SAHA and ZOL, or other inhibitors of the mevalonate pathway, as an effective strategy for anticancer therapy.

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

“…In a further study, the maximum dose of 100 mM ZA triggered apoptosis only marginally in LNCaP cells, as assessed by flow cytometry. 17 The present data point to the cell-cycle regulating protein cyclin E as a relevant target of ZA. It has been shown that cyclin E promotes PC cell proliferation through activation of the PI3K/Akt 1h-membrane 1h-chamber 24h-membrane 24h-chamber 1h-membrane 1h-chamber 24h-membrane 24h-chamber 1h-membrane 1h-chamber 24h-membrane 24h-chamber Figure 4.…”

Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

“…SAHA was effective at decreasing AR v567es in the presence and absence of DHT ( Figure 8, B and C). Although SAHA decreased AR v567es protein levels in the LuCaP 86.2 cells, the resulting decrease in growth (Figure 8D) cannot be conclusively attributed to loss of AR v567es , since histone deacetylases have multiple effects on cells that result in suppression of cell proliferation (17,18).…”

Molecular mechanisms linking geranylgeranyl diphosphate synthase to cell survival and proliferation

“…While GGDPS expression is ubiquitous and its enzymatic product is often required for proliferation (Benford et al, 1999, van de Donk et al, 2003, Inoue et al, 2005, Brinkkoetter et al, 2006, Baulch-Brown et al, 2007, Sonnemann et al, 2007, Wiemer et al, 2007, Yanae et al, 2011, Tsubaki et al, 2013, Zafar et al, 2014), there is only limited evidence, as described in the preceding paragraph, to suggest a higher degree of GGDPS mutation in malignant cells relative to normal cells. Therefore, GGDPS inhibitors could be best classified as anti-metabolites targeting membrane domain proteins (Bennis et al, 1993, Mo and Elson, 2004).…”