The neuropeptide [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P has emerged as a significant molecule in the field of cancer research, particularly in the context of small cell lung cancer (SCLC). This peptide has been identified as a potent bombesin antagonist and has shown promising results in inhibiting the growth of human cancer cells both in vitro and in vivo1467. The following analysis delves into the mechanism of action of this substance P derivative and explores its various applications across different fields.
The mechanism of action of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P involves multiple pathways. It has been shown to inhibit DNA synthesis induced by gastrin-releasing peptide and other bombesin-like peptides, which are known to act as autocrine growth factors in certain tumors1. This inhibition is achieved through the blockade of the bombesin/gastrin-releasing peptide receptor, as evidenced by the reduction in cross-linking of the receptor component proteins and the inhibition of calcium mobilization12. Furthermore, the peptide has been found to act as a biased agonist, selectively activating certain guanine nucleotide-binding proteins through the receptor while blocking others2. This dual function as an antagonist and agonist suggests a complex interaction with neuropeptide and chemokine receptors, leading to varied cellular responses such as apoptosis, cytoskeletal changes, and cell migration24.
Additionally, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P differentially modulates bombesin-stimulated phospholipase Cβ and mitogen-activated protein (MAP) kinase activity, indicating its role in signal transduction pathways3. The peptide's ability to inhibit MAP kinase activation at low bombesin concentrations, but not at higher concentrations, further underscores its nuanced influence on cellular processes3.
The primary application of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P has been in the field of cancer research, where it has demonstrated efficacy in inhibiting the growth of SCLC cells147. The peptide induces apoptosis in lung cancer cell lines, which is a critical pathway for the antiproliferative action of this compound4. Its broad-spectrum antagonistic properties extend to other neuropeptides and growth factors, suggesting potential therapeutic implications for various types of cancer57.
The in vivo metabolism and distribution of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P have been studied in xenograft-bearing mice, revealing a long plasma half-life and widespread tissue distribution6. The findings suggest that therapeutic concentrations of the peptide could potentially be targeted to primary lung tumors, highlighting its relevance in drug delivery systems6.
While the peptide exhibits potent antiproliferative effects on tumor cells, it appears to have a more moderate impact on normal cell growth7. This differential effect is crucial for minimizing potential side effects and enhancing the therapeutic index of the peptide as a cancer treatment7.
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