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Human acute myeloid leukemia cells express Neurokinin-1 receptor, which is involved in the antileukemic effect of Neurokinin-1 receptor antagonists

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Summary

The substance P/neurokinin-1 receptor system has been implicated in tumor cell proliferation. Neurokinin-1 receptor has been identified in different solid tumors but not frequently in hematopoietic malignant cells. We investigated the presence of the Neurokinin-1 receptor in acute myeloid leukemia cell lines (KG-1 and HL-60), demonstrating that acute myeloid leukemia cell lines overexpress the truncated Neurokinin-1 receptor isoform compared with lymphocytes from healthy donors. Using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) method, we demonstrated that substance P induced cell proliferation in both acute myeloid leukemia cell lines. We also observed that four different Neurokinin-1 receptor antagonists (L-733,060, L-732,138, CP 96–345 and aprepitant) elicited inhibition of acute myeloid leukemia cell growth lines in a concentration-dependent manner, while growth inhibition was only marginal in lymphocytes; the specific antitumor action of Neurokinin-1 receptor antagonists occurs via the Neurokinin-1 receptor, and leukemia cell death is due to apoptosis. Finally, administration of high doses of daily intraperitoneal fosaprepitant to NOD scid gamma mice previously xenografted with the HL60 cell line increased the median survival from 4 days (control group) to 7 days (treated group) (p = 0.059). Taken together, these findings suggest that Neurokinin-1 receptor antagonists suppress leukemic cell growth and may be considered to be potential antitumor drugs for the treatment of human acute myeloid leukemia.

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Authors and Affiliations

  1. Department of Hematology, Pediatric Hematology, Instituto de Biomedicina (IBIS / CISC / CIBERONC), University Hospital Virgen del Rocío, Seville, Spain

    A. Molinos-Quintana

  2. University Hospital Virgen del Rocío, Sevilla, Spain

    P. Trujillo-Hacha

  3. Department of Hematology, Instituto de Biomedicina de Sevilla (IBIS / CISC / CIBERONC CB16/12/00480), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Seville, Spain

    J. I. Piruat, J. A. Bejarano-García, E. García-Guerrero & J. A. Pérez-Simón

  4. Research Laboratory on Neuropeptides (IBIS), University Hospital Virgen del Rocío, Av. Manuel Siurot s/n, 41013, Seville, Spain

    Miguel Muñoz

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Correspondence to Miguel Muñoz.

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Conflict of interest

Authors: A Molinos-Quintana, P Trujillo-Hacha, JI Piruat, JA Bejarano-García, E García-Guerrero and JA Pérez-Simón declare that they have no conflict of interest.

M Muñoz declares that he has a conflict of interest: USPTO Application no. 20090012086 ‘Use of non-peptidic NK-1 receptor antagonists for the production of apoptosis in tumor cells’.

Ethical approval

All applicable international, national and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving human material or animal samples were approved by the Ethical Committee for Clinical Research of the University Hospital Virgen del Rocío (Seville, Spain) and were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

All samples from volunteer healthy donors were obtained from the regional blood donation center of the University Hospital Virgen del Rocío, and informed consent was obtained from all individual participants included in the study.

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Molinos-Quintana, A., Trujillo-Hacha, P., Piruat, J.I. et al. Human acute myeloid leukemia cells express Neurokinin-1 receptor, which is involved in the antileukemic effect of Neurokinin-1 receptor antagonists. Invest New Drugs 37, 17–26 (2019). https://doi.org/10.1007/s10637-018-0607-8

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