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Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line

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Summary

Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well understood. Previous work has demonstrated that Apomine induces cell death by activation of caspase-3 in several cancer cell types. However, we have demonstrated that Apomine induces cell death in the A375 human melanoma cell line through a novel membrane-mediated mechanism that is independent of caspase-3 activation. This mechanism of membrane lysis may apply to other bisphosphonates and may be an important mechanism for overcoming resistance to apoptosis. Interestingly, Apomine-mediated cell death in the A375 and UACC 3093 human melanoma cell lines is also independent of N-Ras farnesylation, which was a previously described mechanism of action for Apomine in other cancer cell types. These data suggest that Apomine induces cell death through a novel plasma membrane-mediated cytolytic pathway, independent of caspase-3 activation and N-Ras farnesylation.

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Acknowledgments

These studies were supported by Grant PHS CA27502 and CA23074 from the National Institutes of Health, Bethesda, MD. The authors would like to thank Pam M. Pollock, Ph.D., for the sequencing of N-Ras in the UACC 3093 human melanoma cell line and Terry H. Landowski, Ph.D., for critical reading and editing of this manuscript.

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Authors and Affiliations

  1. Arizona Cancer Center, The University of Arizona, 1515 N, Campbell Avenue, Tucson, AZ, 85724, USA

    Alan Pourpak, Robert T. Dorr, Ross O. Meyers & Steven P. Stratton

  2. Department of Pharmacology, The University of Arizona, 1515 N, Campbell Avenue, Tucson, AZ, 85724, USA

    Alan Pourpak & Robert T. Dorr

  3. Department of Nutritional Sciences, The University of Arizona, 1515 N, Campbell Avenue, Tucson, AZ, 85724, USA

    Ross O. Meyers

  4. Department of Medicine, The University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ, 85724, USA

    Steven P. Stratton

  5. Department of Radiation Oncology, Stanford University, 269 Campus Drive, Stanford, CA, 94305, USA

    Marianne B. Powell

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  1. Alan Pourpak
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  2. Robert T. Dorr
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  5. Steven P. Stratton
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Correspondence to Steven P. Stratton.

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Pourpak, A., Dorr, R.T., Meyers, R.O. et al. Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line. Invest New Drugs 25, 107–114 (2007). https://doi.org/10.1007/s10637-006-9015-6

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  • DOI: https://doi.org/10.1007/s10637-006-9015-6

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