Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide–drug conjugate via activating somatostatin receptor type II

Sun, Lichun; Qian, Qingqing; Sun, Guangchun; Mackey, L. Vienna; Fuselier, Joseph A.; Coy, David H.; Yu, Cui‐Yun

doi:10.3109/1061186x.2015.1066794

Cited by 42 publications

(38 citation statements)

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“…Previous studies suggested effects on a transcriptional level via DNMT and HDAC inhibition (26,27) and on a translational level via HDAC inhibition (28). In the present study, we confirmed these findings and expanded the principle to the functional level in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 88%

Upregulation of Key Molecules for Targeted Imaging and Therapy

et al. 2016

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Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches. Methods: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr 2 ). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo. Results: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr 2 on transcriptional, translational, and functional levels in a time-and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr 2 upregulation improved the tumor-to-background and tumor-tokidney ratios, which are the key determinants of successful sstr 2 -targeted imaging and radiopeptide therapy. Conclusion: We present an approach that uses epigenetic modifiers to improve sstr 2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.

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Section: Discussionsupporting

confidence: 88%

Upregulation of Key Molecules for Targeted Imaging and Therapy

et al. 2016

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“…Previous studies on HDAC inhibition of NET cells have shown activation of Notch1 signalling after VPA treatment. It was also proposed that Notch1 activation is a crucial step in VPA-induced growth inhibition of NET cells [30,31,32]. In the present study, however, pathway analysis identified Notch1 as a significantly affected upstream regulator in GOT1 cells only, while the magnitude of activation was low (Z score = 0.3).…”

Section: Resultscontrasting

confidence: 47%

“…However, at this time point, VPA induced upregulation of NOTCH2 expression in GOT1 and BON cells, suggesting activation of Notch family members. A recent study analysed the expression of Notch1 in BON cells over time and showed that Notch1 expression was upregulated only after chronic exposure to VPA [32]. That study also provided evidence that activation of Notch1 does not account for all the anti-tumour effects of VPA treatment.…”

Section: Discussionsupporting

confidence: 48%

“…Here, we have shown that treatment with VPA significantly upregulates the expression of SSTR2 in NET cells, which may be a means of counteracting SSTR resistance and enhancing the effect of somatostatin analogues and PRRT. A recent study showed upregulation of SSTR2 in BON cells after VPA and demonstrated a synergistic effect between VPA and the SSTR2-specific camptothecin-somatostatin conjugate, highlighting the potential of HDAC inhibition for combination therapy in NETs [32]. …”

Section: Discussionmentioning

confidence: 99%

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Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

et al. 2015

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Background/Aims: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. Methods: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. Results: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. Conclusions: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease.

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“…This effect was however only prominent at high doses, suggesting that observed effects might be due to off-target activity. HDAC inhibition has also previously been suggested as a treatment option for GEPNET patients (Baradari et al 2006, Sun et al 2016.…”

Section: :3mentioning

confidence: 99%

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Hofving¹,

Arvidsson²,

Almobarak³

et al. 2018

Endocrine-Related Cancer

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Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

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Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide–drug conjugate via activating somatostatin receptor type II

Abstract: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.

Cited by 42 publications

References 42 publications

Upregulation of Key Molecules for Targeted Imaging and Therapy

Upregulation of Key Molecules for Targeted Imaging and Therapy

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

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