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Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma

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Abstract

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in combination with cisplatin or pemetrexed. We used four MPM cell lines (MS589, H28, H2052, JMN), a normal mesothelial cell line (HM3), and a lung cancer cell line (H23) in survival studies utilizing bortezomib, cisplatin, and pemetrexed alone and in combination by administering concurrently or by varying the order of administration. We determined the effect of bortezomib on the cell cycle, apoptosis, and on the expression of cell cycle proteins p21/WAF1 and p27/KIP1 and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. Bortezomib was highly cytotoxic to MPM cells and induced both G2/M and G1/S cell cycle arrest. Apoptosis increased in a concentration- and time-dependent manner in 3 of 4 MPM cell lines. Bortezomib stabilized or increased protein levels of p21/WAF1 and IAP-1 and to a lesser degree p27/KIP1, IAP-2, XIAP, and survivin. In combination studies with cisplatin, bortezomib was generally synergistic at high concentrations and antagonistic at low concentrations. Bortezomib increased the cytotoxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in MPM patients alone or in combination with standard chemotherapy but the order of administration is likely to be important. This study justifies further evaluation of bortezomib in MPM.

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Acknowledgments

This work was partly funded by grants to G.J.G., R.B., and B.Y.Y. from The International Mesothelioma Program (http://www.impmeso.org), to G.J.G. from the Mesothelioma Applied Research Foundation (MARF), to R.B. from the NCI (CA120528 and CA100315).

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Authors and Affiliations

  1. The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA

    Gavin J. Gordon & Raphael Bueno

  2. The Thoracic Surgery Oncology Laboratory, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA

    Madhubalan Mani, Gautam Maulik & Lipi Mukhopadhyay

  3. Department of Medicine, Hematology/Oncology Unit, Massachusetts General Hospital, Boston, MA, USA

    Beow Y. Yeap

  4. Section of Hematology/Oncology, Department of Medicine, University of Chicago Cancer Research Center, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, IL, USA

    Hedy L. Kindler & Ravi Salgia

  5. Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA

    David J. Sugarbaker

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  1. Gavin J. Gordon
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  2. Madhubalan Mani
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Correspondence to Gavin J. Gordon.

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Gordon, G.J., Mani, M., Maulik, G. et al. Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma. Cancer Chemother Pharmacol 61, 549–558 (2008). https://doi.org/10.1007/s00280-007-0500-1

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  • DOI: https://doi.org/10.1007/s00280-007-0500-1

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