Combined histone deacetylase and cyclooxygenase inhibition achieves enhanced antiangiogenic effects in lung cancer cells

Abstract

PGE2 is an important pro-angiogenic and pro-proliferative cytokine and the key enzymes modulating its levels, COX-2 and 15-PGDH play important opposing roles in carcinogenesis. Previously we found loss of 15-PGDH expression in lung cancer and its reactivation leads to strong in vivo tumor-suppressive effect via an antiangiogenic mechanism. Here we find that HDAC inhibitors (HDACI), such as trichostatin A (TSA) and vorinostat could reactivate 15-PGDH expression but overall induce PGE2 generation and this is the result of concomitant induction of COX-1 and 2 leading to functional promotion of endothelial cell proliferation and capillary formation. Direct TSA treatment inhibits endothelial cell proliferation and capillary formation in our study in line with prior reports as HDACIs have been shown to directly inhibit angiogenesis. The elevation of PGE2 levels induced by HDACI is potently neutralized by indomethacin (INN) or celecoxib co-treatment and accordingly, angiogenesis is more effectively inhibited when using conditioned medium of co-treatment than either alone confirming that this effect is mediated via the PGE2 axis. Accordingly, blockage of EP2/4 receptors mitigates the stimulation of angiogenesis by excessive PGE2 generation mediated by TSA. In this study, we identify a potentially adverse effect of HDACIs through induction of both 15-PGDH and COX-2 leading to elevated PGE2 levels and thereby stimulation of angiogenesis. Co-treatment of TSA and INN shows more potent anti-angiogenic effects by inducing 15-PGDH and inhibiting COX-2. Overall, our results suggest that combined HDACI and COX inhibition should be explored clinically to achieve more meaningful benefits from HDACI therapy in lung cancer.

The Anti-Tumor Effect of HDAC Inhibition in a Human Pancreas Cancer Model Is Significantly Improved by the Simultaneous Inhibition of Cyclooxygenase 2

“…As a consequence, class I HDAC inhibition could induce the transcriptional activation of NF-kB-driven genes. Consistently, a significant COX-2 induction was recently showed in lung cancer cells following trichostatin A or SAHA treatment [27]. Here, we showed, for the first time, that the class I HDAC chemical inhibitor MS-275 and selective silencing of both HDAC1 and HDAC3 are able to induce the transcription of COX-2 gene and the accumulation of the functional enzyme independently of the KRAS status.…”

“…For example, a recent study demonstrated that pan-HDAC inhibitors induce cyclooxygenase-2 (COX-2) expression in lung cancer cells, leading to a stimulation of endothelial cell proliferation [27]. Since COX-2 has been also associated to pancreatic cancer cell proliferation [28] or tumor growth [29]–[31], we hypothesized that COX-2 overexpression may also be induced in PDAC when treated with HDAC inhibitors, leading to reduced efficiency and hence therapeutic failure.…”

Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

“…While dual-acting compounds comprising NSAIDs and other agents exist 20 , none contain HDACi and NSAIDs combined as a single component. Moreover, results from in vitro studies suggest that enhanced cytotoxic effect could be achieved by combining NSAIDs and HDACi in cancer cell lines 21 . In this study, we designed and synthesized bifunctional compounds with HDAC and COX-2 inhibitory activities.…”

Insulin‐like growth factor binding protein‐4 inhibits cell growth, migration and invasion, and downregulates COX‐2 expression in A549 lung cancer cells

“…In our studies, we tried to find whether COX-2 is regulated by IGFBP-4 in lung cancer inflammatory microenvironment by the addition of LPS to the cell media. COX-2 inhibition suppressed cell proliferation and improved antiangiogenic and apoptotic effects in lung cancer (Qiu et al, 2012;Wang et al, 2013). IGFBP-4 neutralizing antibody treatment could increase LPSinduced COX-2 protein expression in lung cancer cells.…”

“…COX-2 as an inflammatory mediator promotes cell growth, migration, invasion, and tumor progression to metastasis (Liu et al, 2001;Larkins et al, 2006;Hu et al, 2009;Lyons et al, 2011;Karavitis et al, 2012). COX-2 inhibition suppressed cell proliferation and improved antiangiogenic and apoptotic effects in lung cancer (Qiu et al, 2012;Wang et al, 2013). In addition, IGFBP-4 was downregulated and COX-2 was upregulated in lung cancer tissue compared to matched adjacent normal tissues.…”