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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Kidd, M; Schally, AV; Pfragner, R; Malfertheiner, MV; Modlin, IM.
Inhibition of proliferation of small intestinal and bronchopulmonary neuroendocrine cell lines by using peptide analogs targeting receptors.
Cancer. 2008; 112(6): 1404-1414.
Doi: 10.1002/cncr.23303
[OPEN ACCESS]
Web of Science
PubMed
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- Co-authors Med Uni Graz
- Pfragner Roswitha
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- Abstract:
- BACKGROUND: Currently, no consistently effective therapy is available to inhibit cell proliferation or metastasis of neuroendocrine tumor (NET) disease. The effects of 4 novel peptides were analyzed: a targeted cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH) analog (AN-152), a targeted cytotoxic analog of somatostatin (AN-238), and 2 antagonists of growth hormone-releasing hormone (GH-RH) on 3 NET (carcinoid) cell lines that expressed respective peptide receptors. METHODS: The effects of the compounds were evaluated on cell proliferation in vitro using MTT uptake and Ki67 expression, apoptosis (caspase 3 expression and activity), and cell cycle parameters (DNA distribution). RESULTS: Proliferation of the LH-RH receptor-expressing lung NET, NCI-H720 line, was inhibited 2-fold by AN-152 containing doxorubicin compared with the chemotherapy alone (IC50 of 9.1 nM vs 24 nM). This was associated with a reduction in Ki67 transcript and an increase in both caspase 3 mRNA levels and activity. Proliferation of the GH-RH receptor expressing lung NET, NCI-H727 line, was inhibited by both GH-RH antagonists, the effects being mediated through changes in Ki67 expression, but not in caspase 3-mediated apoptosis. The small intestinal NET, KRJ-I line, was 8x more sensitive to inhibition by AN-238 than to 2-pyrolino-doxorubicin, reflected by increased caspase 3 transcript as well as activity. AN-238-mediated growth inhibition culminated in complete G1 arrest. CONCLUSIONS: The data demonstrate GH-RH antagonists or peptide-linked antineoplastic agents such as AN-152 and AN-238 are effective inhibitors of NET proliferation in vitro. Because peptide receptors such as those for GH-RH, LH-RH, and SST subtypes are commonly expressed by NETs, the development of antineoplastic agents targeted to specific tumor receptors may provide a more efficacious strategy than systemic chemotherapeutic agents currently in use.
- Find related publications in this database (using NLM MeSH Indexing)
- Apoptosis - drug effects
- Bronchial Neoplasms - drug therapy
- Carcinoid Tumor - drug therapy
- Caspase 3 - metabolism
- Cell Cycle - drug effects
- Cell Proliferation - drug effects
- Cytotoxins - pharmacology
- Doxorubicin - analogs and derivatives
- Flow Cytometry -
- Gonadotropin-Releasing Hormone - analogs and derivatives
- Growth Hormone-Releasing Hormone - antagonists and inhibitors
- Humans -
- Intestinal Neoplasms - drug therapy
- Intestine, Small - drug effects
- Ki-67 Antigen - genetics
- Lung Neoplasms - drug therapy
- Pyrroles - pharmacology
- RNA, Messenger - genetics
- Receptors, LHRH - antagonists and inhibitors
- Receptors, Somatostatin - antagonists and inhibitors
- Reverse Transcriptase Polymerase Chain Reaction -
- Tumor Cells, Cultured -
- Find related publications in this database (Keywords)
- AN-152
- AN-238
- bronchopulmonary carcinoid
- carcinoid
- cytotoxic peptide analogs
- doxorubicin
- drug sensitivity
- H720
- H727
- KRJ-I
- MZ-5-156
- neuroendocrine tumor
- somatostatin