Malignant pleural mesothelioma is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently being studied for its effects on various types of cancer, but has not been studied extensively in mesothelioma.In this report, the researchers determine the biological and molecular response of mesothelioma cells to bortezomib alone and in combination with cisplatin and with pemetrexed (Alimta).
The researchers used mesothelioma cell lines, a normal mesothelial cell line, and a lung cancer cell line in survival studies designed to test the effect of bortezomib on mesothelioma. They also tested bortezomib with cisplatin alone, and with pemetrexed alone. They also tested bortezomib by combining it with Alimta/cisplatin by administering it concurrently or by varying the order of administration.
They determined the effect of bortezomib on: the cell’s life cycle cycle, apoptosis (cell death), on the expression of cell cycle proteins p21/WAF1 and p27/KIP1, and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. These proteins are important for cells, and if they can be affected in the proper way, the cancer cells will die.
Bortezomib was highly cytotoxic to mesothelioma cells and induced cell cycle arrest. Apoptosis increased in a in 3 of 4 mesothelioma 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 at high concentrations worked well to kill cancer cells, and did not work well with cisplatin at low concentrations. Bortezomib increased the toxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in pleural mesothelioma 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.
From: Cancer Chemother Pharmacol. 2007 May 24
Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma.
Gordon GJ, Mani M, Maulik G, Mukhopadhyay L, Yeap BY, Kindler HL, Salgia R, Sugarbaker DJ, Bueno R.
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, firstname.lastname@example.org.