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. 2013 May 22;371(1-2):189-94.
doi: 10.1016/j.mce.2012.12.011. Epub 2012 Dec 23.

Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells

C G Ziegler  1 , M Ullrich, A V Schally, R Bergmann, J Pietzsch, L Gebauer, K Gondek, N Qin, K Pacak, M Ehrhart-Bornstein, G Eisenhofer, S R Bornstein
Affiliations

Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells

C G Ziegler et al. Mol Cell Endocrinol. .

Abstract

Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing.

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Figures

Figure 1
Figure 1
Immuohistochemical analyses: protein expression of the neuropeptide hormone receptors on mouse pheochromocytoma cells (A-F). Negative control (A). MPC express sst2 (B), GHRHR (C) and LHRHR (D) and on MTT cells we found a pronounced expression of GHRHR (E) and LHRHR (F) (Scale bars: 20 µm).
Figure 2
Figure 2
Anti-tumor effects of peptide analogs targeting ss2, LHRHR and GHRHR in MPC. AN-162 and AN-238 significantly influenced MPC cell viability over 24–72h (A) and highly significant increased caspase 3/7 activity (B) over 24–72h (10−6 mol/l). Similarly, GHRH antagonist MIA-602, LHRH antagonist Cetrorelix and LHRH analog AN-152 reduced MPC cell viability (C). AN-152 also significantly increased programmed MPC cell death (D) (n= 3–6, *P < 0.05, **P < 0.01, ***P < 0.001 as compared to control for all assays).
Figure 3
Figure 3
Anti-tumor effects of peptide analogs targeting LHRHR and GHRHR in MTT cells. AN-152 (10−6–10−7 mol/l) highly significant reduced MTT cell viability (A) and induced cell apoptosis (B) over 24–72h. (C) MIA-602 (10−5 mol/l) significantly reduced cell viability of more malignant MTT cells (48–72h). (D) Ultrastructural analyses. Confirmation of pro-apoptotic mode of cell death induced by AN-152, including shrinking of the cytoplasm away from the plasma membrane, apoptotic bodies, internucleosomal DNA fragmentation, or condensation of the cytoplasm while retaining mitochondria and endomembrane structure (Scale bar, 0.2 µm); DCV, dense-core vesicles; MIT, mitochondria; Nuc, nucleus.
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