Schedule-Dependent Interaction between the Proteosome Inhibitor Bortezomib and the EGFR-TK Inhibitor Erlotinib in Human Non-small Cell Lung Cancer Cell.

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Schedule-Dependent Interaction between the Proteosome Inhibitor Bortezomib and the EGFR-TK Inhibitor Erlotinib in Human Non-small Cell Lung Cancer Cell Lines Bilal Piperdi, MD, Yi-He Ling, PhD, Roman Perez-Soler, MD Journal of Thoracic Oncology Volume 2, Issue 8, Pages 715-721 (August 2007) DOI: 10.1097/JTO.0b013e3180f60bb3 Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Combined cytotoxic effect of erlotinib and bortezomib in human non-small cell lung cancer cell lines. The cells were exposed for 72 hours to a range of combined concentrations of erlotinib and bortezomib. The combination index (CI) was plotted against fractional effect (Calcusyn software). See Materials and Methods section for details. Journal of Thoracic Oncology 2007 2, 715-721DOI: (10.1097/JTO.0b013e3180f60bb3) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Combined effect of erlotinib and bortezomib in the H358 bronchoalveolar cell line. Log phase growing cell were exposed to defined concentrations of erlotinib, bortezomib, or their combination. Cell survival was measured by colony count and expressed as fraction compared with baseline over a time course (A). The percentage of apoptosis measured by flow cytometry was plotted over a time course (B). All values are mean ± SD of three independent experiments. Journal of Thoracic Oncology 2007 2, 715-721DOI: (10.1097/JTO.0b013e3180f60bb3) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Schedule-dependent interaction between bortezomib (B) and erlotinib (E) in H358 human bronchoalveolar cells. Cells were treated with either bortezomib (B) or erlotinib (C) alone or in combination either concomitantly (D) or sequentially 24 hours apart (E, F). Cell cycle analysis was performed as mentioned in the Materials and Methods section. Journal of Thoracic Oncology 2007 2, 715-721DOI: (10.1097/JTO.0b013e3180f60bb3) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Effects of schedule-dependent interaction between bortezomib and erlotinib on cell survival in H358 (A) and A549 (B) cells. Cells were treated with either bortezomib (B) or erlotinib (E) alone or in combination either concomitantly (B+E) or sequentially 24 hours apart (B→E; E→B). Cell survival analysis (A, B) and apoptosis (C, D) was performed as mentioned in the Materials and Methods section. The results are average of three independent experiments (mean ± SD) and expressed as the percentage of survival compared with control (100%). Journal of Thoracic Oncology 2007 2, 715-721DOI: (10.1097/JTO.0b013e3180f60bb3) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Erlotinib pre-exposure prevents bortezomib-induced caspase 3 activation and poly(adenosine diphosphate ribose) polymerase (PARP) cleavage in H358 BAC cells. Cells were treated with either control (C), bortezomib (B), or erlotinib (E) alone or in combination either concomitantly (B+E) or sequentially 24 hours apart (B→E, E→B) Caspase 3 activation and PARP cleavage were determined by Western blot analysis as mentioned in the Materials and Methods section. Journal of Thoracic Oncology 2007 2, 715-721DOI: (10.1097/JTO.0b013e3180f60bb3) Copyright © 2007 International Association for the Study of Lung Cancer Terms and Conditions