Anticancer activity of a peptide combination in gastrointestinal cancers targeting multiple neuropeptide receptors

Abstract

A novel peptide combination consisting of four synthetic neuropeptide analogs of Vasoactive Intestinal Peptide (VIP), Bombesin, Substance P and Somatostatin has been found to have potent anticancer activity in vitro and in vivo. The receptors of these four neuropeptides are known to be over expressed in various cancers. We have found the presence of native neuropeptides in the culture supernatant of the primary tumor cells of human colon adenocarcinomas. It was further demonstrated by receptor-ligand assays that not only do these tumor cells synthesize and secrete four peptide hormones but also possess specific high affinity receptors on their surface. Screening a large panel of analogs to the four peptide hormones on tumor cell proliferation led to the identification of four cytotoxic analogs, the combination of which was code-named DRF7295. The design and synthesis of the peptide analogs have been described in this paper. In vitro anticancer activity of DRF7295 was studied in a large panel of human tumor cells. Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to be most sensitive to DRF7295 with moderate activity seen in glioblastoma, prostate, leukemia and those of oral cancer cells. Efficacy studies in xenograft models of colon and duodenum resulted in T/C% of less than 40%, which is indicative of strong tumor regressing potential of DRF7295 in gastrointestinal cancers. Acute and long-term toxicity studies as well as safety pharmacology studies conducted indicate the safety of the drug upon systemic administration with no significant adverse pharmacological effects.

Screening of a Specific Peptide Binding to VPAC1 Receptor from a Phage Display Peptide Library

“…In our previous study, we first reported that testes-specific protease 50 (TSP50) was abnormally and highly expressed in CRC and represented a potential effective predictor of poor prognosis in CRC patients, making it an attractive novel target for molecular imaging and therapy [30]. Several previous reports demonstrated that the VPAC1 receptor is highly expressed in CRC and plays a major role in the progression of CRC [11], [14], making it one of the most promising novel candidate markers for early CRC detection. Therefore, the screening and identification of peptides that specifically bind to the VPAC1 receptor will aid the development of novel probes for CRC detection and therapy.…”

“…The difference in the cell surface profile between cancer cells and their normal counterparts can be utilized as a molecular signature for targeted imaging. Furthermore, the overexpressed VPAC1 receptors play a major role in the progression of a number of malignancies, including cancers of the lung, brain, gut, and prostate in addition to neuroblastomas [13], [14], and they mediate tumor angiogenesis through the transactivation of epidermal growth factor receptor (EGFR) and the expression of vascular endothelial growth factor (VEGF) [15], [16]. Thus, these data indicate that the VPAC1 receptor is a potential target for tumor diagnosis and therapy.…”

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas

“…Further, they caused partial tumor regression in nude mice xenografts suggesting that they may have use as novel anticancer molecules. DRF 7295 comprises of such novel analogs of the four neuropeptides with in vitro and in vivo efficacy [2]. The inhibition of specific signaling pathways represent a novel approach in cancer drug design.…”

“…A systematic study of some of these peptide growth factors modulating the growth and proliferation of primary human adenocarcinoma cells led to the development of DRF 7295. A combination of four peptide analogs -DRF 7295 exhibited potent and selective anti-neoplastic activity in human adenocarcinoma cells in vitro and in vivo, [2]. These analogs include VIP receptor binding inhibitor, LeuMet-Tyr-Pro-Thr-Tyr-Leu-Lys-OH, the bombesin antagonist, D-Phe-Gln-Trp-Ala-Val-Aib-His-Leu-NH 2 ; the substance P antagonist, D-Arg-Pro-Lys-Pro-D-Phe-Gln-D-Trp-Phe-D-Trp-Leu-Ac5c-NH 2 ; and the somatostatin analogue (with a disulphide bond between Cys and Pen amino acids) D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 .…”

“…These analogs include VIP receptor binding inhibitor, LeuMet-Tyr-Pro-Thr-Tyr-Leu-Lys-OH, the bombesin antagonist, D-Phe-Gln-Trp-Ala-Val-Aib-His-Leu-NH 2 ; the substance P antagonist, D-Arg-Pro-Lys-Pro-D-Phe-Gln-D-Trp-Phe-D-Trp-Leu-Ac5c-NH 2 ; and the somatostatin analogue (with a disulphide bond between Cys and Pen amino acids) D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 . The selection and design of these four peptide analogs have been described earlier [2]. The binding of these peptides to their high affinity bound receptors on tumor cells causes alteration in the levels of multiple intracellular mediators, which result in the inhibition of cell proliferation and differentiation [3].…”