Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma.
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 G(2)/M and G(1)/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.
Gordon
Gavin J
GJ
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. ggordon@partners.org
Mani
Madhubalan
M
Maulik
Gautam
G
Mukhopadhyay
Lipi
L
Yeap
Beow Y
BY
Kindler
Hedy L
HL
Salgia
Ravi
R
Sugarbaker
David J
DJ
Bueno
Raphael
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D007426:Genes, Intracisternal A-Particle / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001897:Boronic Acids; D005971:Glutamates; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000068437:Pemetrexed; D006147:Guanine; D000069286:Bortezomib; D002945:Cisplatin