Investigation of cancer cell lines for peptide receptor-targeted drug development

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.

Notch1-Mediated Tumor Suppression in Cervical Cancer with the Involvement of SST Signaling and Its Application in Enhanced SSTR-Targeted Therapeutics

“…Thus, interest has increased in targeted therapeutics for this cancer type [39]. SSTR2-targeted cancer chemotherapy has been applied successfully to develop novel, safe, and efficacious drugs in treating advanced cancers [36,40,56]. In the present study, the finding that GPCRs such as SSTR2 and GRPR were activated by Notch1 signaling provides an opportunity for an enhanced receptor-targeted or multiple receptor subtype-targeted cancer therapy.…”

Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

“…Although numerous studies have been performed to assess the effect of GI hormones/neurotransmitters on growth of various cancers [15], few studies have focused on their effect in Foregut NETs/PETs proliferation [13,38–42]. Somatostatin receptor agonists reduce growth of a number of NETs [3,36,43,44], as well as antagonists of CCK2R inhibit gastric carcinoid tumor growth [42]. In the EC cell line, KRJ-I cell line and in the broncho-pulmonary NET cell line, NCH720, serotonin stimulates cell proliferation and the synthesis of several growth factors [41].…”

“…Moreover, treatment with Gefitinib (Iressa, Astra Zeneca) or AG1478, inhibitors of EGFR [31], completely blocks BON cell basal proliferation and induces apoptosis [11]. Among the substances synthesized and secreted, BON cells produce serotonin and several peptides such as neurotensin (NT) and bombesin [45] and display high bombesin receptor (GRPR, BRS-3) and high VIP receptor (VPAC1) densities, as well as for somatostatin receptors (sst1, 2, 5) [43,46]. To confirm our results of the importance of EGFR trasactivation in BON cells and establish as it a common mechanism occurring in neuroendocrine tumors, we also evaluated the effect of GI hormones/neurotransmitters in other two Foregut NET/PET cell lines: the human somatostatinoma QGP-1 and the rat islet cell tumor Rin-14B.…”

Anti-Convulsant Drug Valproic Acid in Cancers and in Combination Anti-Cancer Therapeutics

“…These new peptide-drug conjugates could target the specific GPCRs on cancer cell surfaces and quickly internalize drugs of interest inside cells [60]. Moreover, these conjugates have been demonstrated capable of improving the non-specific small molecule agent's anti-cancer efficacy while reducing severe toxic side effects and multiple drug resistance [61,62].…”

“…These peptides and antibodies could be used as drug delivery vehicles when coupled with anti-cancer drugs and thus form new receptor-targeted peptide-or antibody-drug conjugates. Especially, certain of these receptors such as SSTR2 and GRPR are highly expressed in many tumor cells or tumor blood vessels [58][59][60] and have been used for receptor-targeted therapeutics. Put together, these findings could provide a novel strategy of receptor-targeted therapy by combining VPA with these receptor-targeted anti-cancer chemotherapeutics such as peptide-drug conjugates and antibody-drug conjugates.…”