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

Abstract

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.

Identification of candidate colon cancer biomarkers by applying a random forest approach on microarray data

“…It was confirmed that IL8 is differentially expressed in colon cancer, and is associated with proliferation, migration, angiogenesis and chemosensitivity in colon cancer cell line models (30). The VIP gene has also been the focus of investigation in many studies ralating to human cancer (31)(32)(33)(34)(35)(36). WDR77, also known as p44, was reported to be related to the differentiation and proliferation in prostate epithelium (37).…”

Bombesin Receptor-Mediated Imaging and Cytotoxicity: Review and Current Status

“…Another approach to attempt to decrease growth of tumor cells expressing GRP receptors was the synthesis of a 40 residue precursor peptide by linking together 4 designed anticancer peptide analogs including a VIP binding receptor inhibitor, a somatostatin agonist, a substance P receptor antagonist and a Bn receptor antagonist ([DPhe 6 , Aib 11 , desMet 14 ]Bn(6–14), [Analog #20, Table 12] through enzyme cleavable Lys-Lys linkers [156,157]. Treatment with this precursor peptide produced the release of each individual peptide analog by the action of enzymes such as PC1 or PC2, so each neuropeptide analog will bind its receptor and inhibit tumor growth.…”

“…When Balb C nude mice xenografted with primary colon tumor cells were treated with the peptide precursor [Analog #20, Table 12], inhibition in tumor growth of 73.7% vs no treated animals was found. When the molecular pathway used to inhibit cellular proliferation in tumors by the precursor peptide was studied [157] in different cancer cell lines, the results showed that the precursor peptide down-regulated cAMP, EGF-dependent cell proliferation and the phosphorylation pERK1/2 in GI carcinomas. It also produced an activation of the apoptotic caspase-3 dependent pathway and induced the p53 tumor suppressor protein.…”

The State-of-the-Art Mechanisms and Antitumor Effects of Somatostatin in Colorectal Cancer: A Review

“…Interesting research on the apoptosis process concerns the use of a combined preparation consisting of four NPs (including SST) called DRF 7295. This peptide caused an increase in p53 levels, downregulation of Bcl-2 levels in Colo205 cells and induction of active caspase-3 in HT-29 cells [ 158 , 159 ].…”

“…Antiangiogenic features were also demonstrated for the DRF 7295, which is a combination of SST with three other NPs (VIP, bombesin and SP). Concerning angiogenesis, this compound caused inhibition of VEGF secretion in HT-29 cells, as well as inhibition of capillary tube-like formation in ECs [ 159 ].…”