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Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo

  1. Author:
    Gills, J.
    Lo Piccolo, J.
    Tsurutani, J.
    Shoemaker, R. H.
    Best, C. J. M.
    Abu-Asab, M. S.
    Borojerdi, J.
    Warfel, N. A.
    Gardner, E. R.
    Danish, M.
    Hollander, M. C.
    Kawabata, S.
    Tsokos, M.
    Figga, W. D.
    Steeg, P. S.
    Dennis, P. A.

  2. Author Address

    NCI, Canc Res Ctr, Med Oncol Branch, Bethesda, MD 20889 USA. NCI, Canc Res Ctr, Mol Therapeut Program, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Pathol Lab, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Clin Pharmacol Program, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Frederick, MD 21701 USA. NCI, Clin Pharmacol Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA.;Dennis, PA, NCI, Canc Res Ctr, Med Oncol Branch, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA.;pdennis@nih.gov
    1. Year: 2007
    2. Date: Sep
  2. Journal: Clinical Cancer Research
    1. 13
    2. 17
    3. Pages: 5183-5194
  4. Type of Article: Article
  5. ISSN: 1078-0432
  1. Abstract:

    Purpose: The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents. Experimental Design: HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non-small cell lung carcinoma (NSCLC) xenografts with biomarker assessment. Results: Three of six HIV protease inhibitors, nelfinavir, ritonavir, and sacluinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 mu mol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but nelfinavir caused the greatest inhibition of endogenous and growth factor-induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis. Conclusions: Nelfinavir is a lead HIV protease inhibitor with pleioitropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, nelfinavir is a Food and Drug Administration-approved drug that could be repositioned as a cancer therapeutic.

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  2. DOI: 10.1158/1078-0432.ccr-07-0161
  3. View record in Web of Science®
  4. WOS: 000249287700035

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