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Paradoxical effects of the autophagy inhibitor 3-methyladenine on docetaxel-induced toxicity in PC-3 and LNCaP prostate cancer cells

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Abstract

Docetaxel was the first chemotherapeutic agent to increase survival time in patients with androgen-resistant prostate cancer. However, it provides only a modest increase in survival and is associated with significant toxicity. Therefore, there is an urgent need to identify potential adjunct therapies. Given the key role of autophagy in both tumour survival and chemoresistance, the impact of autophagy modulation on docetaxel toxicity was tested in vitro. PC-3 and LNCaP cells were pre-treated with the autophagy inhibitor 3-methyladenine (5 mM) and then exposed to various concentrations (0–100 μM) of docetaxel. Cytoxic effects of docetaxel were measured using resazurin reduction to resorufin, whilst autophagy and apoptosis was measured using monodansylcadaverine, annexin V and caspase-3, respectively. Docetaxel produced significant toxicity in PC-3 cells but was not toxic to LNCaP cells. Pre-treatment with the autophagy inhibitor, 3-methyladenine (5 mM) significantly protected PC-3 cells against docetaxel-induced cytotoxicity, increased autophagosome formation and apoptosis measured using monodansylcadaverine, annexin V and caspase-3 fluorescence, respectively. In contrast, 3-methyladenine was toxic by itself in LNCaP cells and also increased autophagic vesicle formation and apoptosis but did not influence docetaxel toxicity in these cells. These paradoxical effects of 3-methyladenine were largely independent of reactive oxygen species production. We show here that modulation of autophagy may influence docetaxel-induced toxicity in prostate cancer cells and these effects may differ between cell lines.

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Acknowledgments

This work was funded by the Griffith Health Institute, Griffith University.

Conflict of interest

The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Griffith Health Institute, Griffith University, Gold Coast Campus, Gold Coast, Queensland, 4222, Australia

      Rebecca D. Pickard, Briohny H. Spencer, Amelia J. McFarland, Nijole Bernaitis, Andrew K. Davey, Anthony V. Perkins & Shailendra Anoopkumar-Dukie

    2. School of Pharmacy, Griffith University, Gold Coast Campus, Gold Coast, Queensland, 4222, Australia

      Rebecca D. Pickard, Briohny H. Spencer, Amelia J. McFarland, Nijole Bernaitis, Andrew K. Davey & Shailendra Anoopkumar-Dukie

    3. School of Medical Science, Griffith University, Gold Coast Campus, Gold Coast, Queensland, 4222, Australia

      Anthony V. Perkins

    4. Centre for Urology Research, Bond University, Robina, Queensland, 4226, Australia

      Russ Chess-Williams, Catherine M. McDermott & Amanda Forbes

    5. Genesis CancerCare, Southport, Queensland, 4215, Australia

      David Christie

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    1. Rebecca D. Pickard
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    Correspondence to Shailendra Anoopkumar-Dukie.

    Additional information

    Rebecca D. Pickard, Briohny H. Spencer and Amelia J. McFarland contributed equally to this work.

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    Pickard, R.D., Spencer, B.H., McFarland, A.J. et al. Paradoxical effects of the autophagy inhibitor 3-methyladenine on docetaxel-induced toxicity in PC-3 and LNCaP prostate cancer cells. Naunyn-Schmiedeberg's Arch Pharmacol 388, 793–799 (2015). https://doi.org/10.1007/s00210-015-1104-7

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    • DOI: https://doi.org/10.1007/s00210-015-1104-7

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