N-Terminal Acylation of Somatostatin Analog with Long Chain Fatty Acids Enhances Its Stability and Anti-Proliferative Activity in Human Breast Adenocarcinoma Cells.

Abstract

The therapeutic potential of peptide drugs has remained unfulfilled due to the unfavorable physicochemical properties of these molecules. Peptides are extremely susceptible to proteolytic degradation in blood and tissues. The hydrophilic nature of peptides severely limits their permeability across hydrophobic cell membranes.2) RC-160, a potent somatostatin analog is one of the most extensively studied therapeutic peptides for its anti-proliferative and anti-secretory activity.D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2 Compared to somatostatin, RC-160 possesses improved anti-proliferative and anti-secretory activity. It is particularly active against breast, prostate, renal and ductal pancreatic cancers and has been successfully used in the therapy of hypersecretory states and AIDS-related diarrhea.3-5) Despite the high potency and specificity of RC-160, its application as a clinically useful drug has been problematic because of its short biological half-life and serious delivery problems. The bioactivity of RC-160 is mediated through high affinity Gprotein coupled somatostatin receptors (SSTRs) on target cells. 4,5) It has been suggested that the inhibitory effect of RC-160 on tumor growth may be mediated directly by SSTRs on cancer cells, or induced indirectly by the inhibition of growth factors such as epidermal growth factor (EGF), insulin like growth factor (IGF)-1, etc. [3][4][5] Although somatostatin analogs like octreotide and RC-160 are longer acting than the native hormone, their biological activity of less than 2 h requires either frequent administration, or sustained release formulation, to attain enhanced anti-proliferative activity and a long-term suppression of hormones like growth hormone (GH) and IGF-1. 6) Formulations of octreotide and somatuline, made by entrapping the peptide in DL-lactide-co-glycollide polymer microspheres 6-10) have been shown to display improved anti-proliferative activity and modulation of GH release but their pharmacokinetic properties are not optimal. 7,8) Somatuline displays an initial burst in drug release whereas octreotide produces an initial delay in peptide release. The administration of these antitumor agents is also limited by their pleotropic nature and side effects like increased incidence of cholesterol gallstones, temporary inhibition and/or delay of insulin release in response to meals and diminished in glucose tolerance in some patients.11) The acute administration of somatostatin agonists has been observed to produce receptor desensitization, which results in diminished therapeutic response and induction of tolerance.11) Hence, there is a need for further modification of these analogs to increase their stability and improve their therapeutic index.Lipophilization (conjugation of fatty acyl moiety) of bioactive peptides, is a novel strategy to increase their stability and biological availability. Unlike sustained release formulations, lipophilization can also impart enhanced receptor selectivity to peptides. [12][13][14] The attachment of fatty acids to pepti...

Effect of acyl donor chain length on isoquercitrin acylation and biological activities of corresponding esters

“…The activity of a compound in a biological system does not only depend on its interaction with cell membranes due to its lipophilicity but also on its affinity for specific cell receptors. For instance, Dasgupta et al [72] showed that in human breast cancer cells, the receptor affinity of somatostatin analogue was not affected by its acylation with palmitic acid, whereas this affinity was reduced when the peptide was acylated with stearic or butyric acids.…”

Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis

“…4 In recent years, several studies have suggested that SST functions as a tumor suppressor gene and possesses potent antitumor and antisecretory activity in several human cancers in vitro and in vivo. [5][6][7][8] Aberrant methylation of promoter CpG islands upstream of tumor suppressor genes is now well established as a major epigenetic mechanism of gene inactivation in tumorigenesis, 9 including ESCC and EAC. 10,11 More recently, data from our laboratory have shown that the SST promoter is methylated in 80% of human colon cancers, and that 5-aza-2 0 -deoxycytidine (5-Aza-dC) reverses SST promoter hypermethylation and restores SST mRNA expression in colon cancer cell lines.…”

Reversible Lipidization Prolongs the Pharmacological Effect, Plasma Duration, and Liver Retention of Octreotide

“…The lipidized form of somatostatin analogue RC-160 has previously been synthesized with one moiety of myristic acid (14 carbons) coupled to the N-terminal residue of RC-160 through a stable amide linkage. When tested in vitro, lipidized RC-160 showed increased stability and enhanced antiproliferation (8)(9)(10). However, no relevant in vivo results have been published so far.…”