Neuropeptide receptors could provide treatment target for chemoresistant SCLC

By Sarah Pritchard, medwireNews Reporter

The discovery of a novel broad spectrum neuropeptide antagonist, peptide–1, which is related to the substance P analogue SP-G, could help develop treatments targeted at chemoresistant small-cell lung cancer (SCLC), indicate study results.

After positively identifying increased CD133 expression in both mouse and human SCLC tissue cell lines after chemotherapy, the study’s researchers noted increased expression of the mitogenic neuropeptide receptors for gastrin-releasing peptide (GRP-R) and arginine vasopressin (AVP) – both of which were sensitive to peptide–1.

CD133 is an important marker of cancer stem-like cells (CSC) in other cancersto which drug resistance is attributed, observe the UK-based research team.

The current finding indicates the analogue “may... have additional benefit as an adjunct to chemotherapy or as a second-line treatment for resistant disease” suggest Tariq Sethi (Kings College London) and co-authors in Cancer Research.

Both SCLC cell lines analysed in the study using in vitro and in vivo modelling techniques expressed the stem cell marker CD133. Cells positive for CD133 positive cells were significantly more proliferative and significantly more resistant to treatment with etoposide than their negative counterparts.

The researchers then sought to identify whether these chemoresistant CD133 positive cells expressed increased GRP and V_1A receptors, to align with a previous finding that that chemoresistant cells show increased sensitivity to neuropeptides GRP and AVP and substance P analogues. The team found this to be true for both cell lines.

Using the substance P analogue SP-G (which was unsuccessful in a phase I clinical trial) as a basis for modification, a novel analogue, peptide–1, emerged to be more effective at inducing apoptosis in both cell lines compared with SP-G.

Indeed, after testing peptide–1 in an in vivo xenograft model of one of the SCLC cell lines for the duration of the study, tumour volume reduced significantly and at least in equivalence with etoposide treatment alone.

Furthermore, in vitro, and in contrast with etoposide, CD133 positive cells were three times more sensitive to peptide–1 compared with unsorted cells, while CD133 negative cells were more than four times less sensitive.

“These results show that chemoresistant CD133-expressing SCLC cells are more sensitive to substance P analogues and suggest these analogues may have potential as anticancer agents with greater efficacy in resistant disease”, conclude Sethi et al.

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