Investigation of cancer cell lines for peptide receptor-targeted drug development
Lichun Sun1, Jing Luo, L Vienna Mackey
1Department of Medicine, Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans, LA 70112-2699, USA. lsun@tulane.edu
Abstract:
Many tumors highly express specific populations of G-protein-coupled receptors (GPCRs) that could be utilized for receptor-targeted therapy. We confirmed significant quantities of mRNAs specific for certain somatostatin (SST), vasoactive intestinal peptide (VIP), and bombesin (BN) receptors in various commercially available tumor cell lines. Very few of the tumor cell lines examined displayed the high receptor-binding affinity despite exhibiting the expression of appropriate mRNAs and proteins of the cognate receptors. However, binding assays establish that some tumor cell lines, such as pancreatic cancer CFPAC-1, prostate cancer DU-145, and pancreatic carcinoid BON, demonstrate high BN receptor binding. BON cells also demonstrate high somatostatin receptor (SSTR) affinity binding. We also found that tumor cell lines, such as BON and host cells expressing SST receptor subtypes 1 or 2 (CHO-R1 or CHO-R2), underwent a decrease in cell surface receptor density in multiple passages. BON and CHO-R2 cells also rapidly internalize a significant proportion of cell surface ligand-receptor complexes. The tumor cells CFPAC-1, DU-145, and BON with high receptor binding could be useful for peptide drug studies. BON cells were further applied to test SST/BN analogs and cytotoxic conjugates. Furthermore, the in vivo antitumor assay showed that the cytotoxic conjugate CPT-SST targeting all SSTR subtypes displayed a potent tumor-suppressive ability to BON tumors expressing multiple SSTR subtypes.
Insights
Tumor cells express G-protein-coupled receptors (GPCRs) for targeted therapy. Specific cell lines show high binding affinity for bombesin (BN) and somatostatin (SST) receptors, proving useful for peptide drug development and in vivo antitumor assays.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Many tumors overexpress specific G-protein-coupled receptors (GPCRs), presenting potential targets for novel therapies.
- While mRNA and protein expression for somatostatin (SST), vasoactive intestinal peptide (VIP), and bombesin (BN) receptors are confirmed in tumor cell lines, high receptor-binding affinity is often lacking.
Purpose of the Study:
- To identify tumor cell lines with high receptor-binding affinity for specific GPCRs, particularly somatostatin (SST) and bombesin (BN) receptors.
- To evaluate the utility of identified tumor cell lines for peptide drug studies and in vivo antitumor assays.
Main Methods:
- Screening of commercially available tumor cell lines for mRNA and protein expression of SST, VIP, and BN receptors.
- Binding assays to determine receptor affinity and specificity in selected tumor cell lines.
- Assessment of cell surface receptor density changes and ligand-receptor complex internalization.
- In vivo antitumor assays using targeted cytotoxic conjugates.
Main Results:
- Pancreatic cancer CFPAC-1, prostate cancer DU-145, and pancreatic carcinoid BON cells exhibited high bombesin (BN) receptor binding.
- BON cells demonstrated high somatostatin receptor (SSTR) binding affinity.
- BON and CHO-R2 cells showed decreased cell surface receptor density and rapid internalization of ligand-receptor complexes.
- A cytotoxic conjugate (CPT-SST) targeting SSTR subtypes demonstrated potent tumor suppression in vivo in BON tumors.
Conclusions:
- Specific tumor cell lines (CFPAC-1, DU-145, BON) with high GPCR binding affinity are valuable models for peptide drug development.
- BON cells serve as a suitable model for testing somatostatin/bombesin analogs and cytotoxic conjugates.
- In vivo studies confirmed the efficacy of SSTR-targeted cytotoxic conjugates in suppressing tumor growth.
