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Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation

Oncogene volume 22, pages 2750–2761 (2003)Cite this article

Abstract

Endogenous, nontelomeric reverse transcriptase (RT) is encoded by two classes of repeated elements: retrotransposons and endogenous retroviruses. Expression of RT-coding genes is generally repressed in differentiated nonpathological tissues, yet is active in the mammalian germ line, embryonic tissues and tumor cells. Nevirapine is a non-nucleoside RT inhibitor with a well-characterized inhibitory activity on RT enzymes of retroviral origin. Here, we show that nevirapine is also an effective inhibitor of the endogenous RT in murine and human cell lines. In addition, progenitor and transformed cells undergo a significant reduction in the rate of cell growth upon exposure to nevirapine. This is accompanied by the onset of differentiation, as depicted in F9 and C2C7 progenitor cells cultures in which nevirapine triggers the expression of differentiation-specific markers. Consistent with this, an extensive reprogramming of cell cycle gene expression was depicted in nevirapine-treated F9 cultures. Furthermore, nevirapine exposure rescued the differentiation block present in acute myeloid leukemia (AML) cell lines and primary blasts from two AML patients, as indicated by morphological, functional and immunophenotypic assays. The finding that an RT inhibitor can modulate cell proliferation and differentiation suggests that RT may represent a novel target in the development of therapeutical approaches to neoplasia.

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Acknowledgements

We dedicate this paper to our late friend and colleague Franco Tatò. We are grateful to Boehringer Ingelheim and Dr Antonello Mai for providing purified nevirapine, Dr Francesco Lo Coco for providing AML patient blasts and Dr Barbara Di Fiore for critical reading of this manuscript. This work was supported by Associazione Italiana per 1a Ricerca sul Cancro, Istituto Superiore di Sanità and Ministero della Salute Italy-USA Program ‘Therapy of Tumors’. IS was supported by a grant from Fondazione Buzzati-Traverso/AIRC.

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  1. Rosamaria Mangiacasale and Carmine Pittoggi: These authors contributed equally to this work

Authors and Affiliations

  1. CNR, Institute of Molecular Biology and Pathology, Rome, Italy

    Rosamaria Mangiacasale, Elisabetta Mattei & Patrizia Lavia

  2. Department of Paediatrics, Obstetrics and Reproductive Medicine, University of Siena, Italy

    Carmine Pittoggi

  3. Istituto Superiore di Sanità, Rome, Italy

    Carmine Pittoggi, Ilaria Sciamanna, Rodolfo Lorenzini & Corrado Spadafora

  4. Department of Medical Histology and Embryology, University ‘La Sapienza’, Rome, Italy

    Angela Careddu, Lorena Travaglini & Clara Nervi

  5. Medical Oncology Unit, Università Cattolica del Sacro Cuore, Rome, Italy

    Matteo Landriscina & Carlo Barone

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  1. Rosamaria Mangiacasale
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Correspondence to Corrado Spadafora.

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Mangiacasale, R., Pittoggi, C., Sciamanna, I. et al. Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation. Oncogene 22, 2750–2761 (2003). https://doi.org/10.1038/sj.onc.1206354

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