Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis Dao M Nguyen, MD, Dominique.

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Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis Dao M Nguyen, MD, Dominique Lorang, PhD, G.Aaron Chen, MS, John H Stewart, MD, Esmail Tabibi, PhD, David S Schrump, MD The Annals of Thoracic Surgery Volume 72, Issue 2, Pages 371-379 (August 2001) DOI: 10.1016/S0003-4975(01)02787-4

Fig 1 Immunofluorescence flow cytometric analysis of surface expression of erbB1 and erbB2 on H358 cells at baseline and after 24 hours of exposure to 17-allylamino geldanamycin (17-AAG) (20 or 80 nmol/L). Depletion of erbB1 (only at 80 nmol/L of 17-AAG) and erbB2 levels after 17-AAG treatment was indicated by significant reduction of erbB1 and erbB2 mean fluorescence intensity and shifting of the curves to the left. Representative data of three independent experiments that yielded similar results are shown. The Annals of Thoracic Surgery 2001 72, 371-379DOI: (10.1016/S0003-4975(01)02787-4)

Fig 2 Enhancement of paclitaxel-mediated cytotoxicity in H358 cells by 17-allylamino geldanamycin (17-AAG) (20 or 40 nmol/L). The magnitude of growth inhibitory effect in cells treated with the drug combination was supraadditive, particularly at low doses of paclitaxel. Data are presented as mean ± standard deviation of four independent experiments, paclitaxel inhibitory concentration at 50% (IC50) values are indicated in the legends. The Annals of Thoracic Surgery 2001 72, 371-379DOI: (10.1016/S0003-4975(01)02787-4)

Fig 3 (A) Caspase 3 activity in H358 cells treated with paclitaxel (50 or 200 nmol/L) alone or in combination with 17-allylamino geldanamycin (17-AAG) (20 nmol/L). Significantly higher levels of caspase 3 activity was observed in H358 cells treated with 17-AAG and paclitaxel combination than those treated with paclitaxel alone. Caspase 3 activity is expressed as fold of increase over baseline levels detected in control cells. Data are presented as mean ± standard deviation of four independent experiments, ∗p < 0.01, ∗∗p < 0.001. (B) Induction of apoptosis of H358 cells treated with paclitaxel (50 or 200 nmol/L) alone or in combination with 17-AAG (20 nmol/L). Apoptosis was quantitated in H358 cells harvested 60 hours after drug treatment by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL) assay. Although 17-AAG at 20 nmol/L failed to induce apoptosis, combining 17-AAG with paclitaxel resulted in up to twofold increase in the induction of apoptosis. Data are presented as mean ± standard deviation of four independent experiments, ∗p < 0.01. The Annals of Thoracic Surgery 2001 72, 371-379DOI: (10.1016/S0003-4975(01)02787-4)

Fig 4 Levels of vascular endothelial cell growth factor (VEGF) in conditioned culture media of H358 cells at baseline or after stimulation with epidermal cell growth factor (EGF) (20 ng/mL) in the presence or absence of 17-allylamino geldanamycin (17-AAG) (20 or 80 nmol/L) or the selective erbB2 tyrosine kinase inhibitor AG825 (25 or 50 μmol/L). Not only did 17-AAG or AG825 strongly inhibit vascular endothelial cell growth factor production by H358 cells at baseline conditions but they also effectively abrogated the upregulation of vascular endothelial cell growth factor production by epidermal cell growth factor. Data are presented as mean ± standard deviation of four independent experiments. #p < 0.01, ##p < 0.001. The Annals of Thoracic Surgery 2001 72, 371-379DOI: (10.1016/S0003-4975(01)02787-4)

Fig 5 Enhancement of paclitaxel tumoricidal effect by 17-allylamino geldanamycin (17-AAG) in nude mice bearing H358 tumor xenografts. Animals were treated with either 10 mg/kg of 17-AAG (A) or 25 mg/kg of 17-AAG (B) in combination with paclitaxel (1 mg/kg) weekly for 4 weeks by intraperitoneal injections. Treatment schedule consisted of paclitaxel one injection/wk or 17-AAG three daily consecutive injections/wk for 4 weeks. Controls were animals treated with mock injection of the phospholipid-based carrier solution, with 17-AAG alone or with paclitaxel alone. Tumor dimensions were measured weekly until sacrifice. Data are presented as mean ± standard deviation, n = 8 per group. (Taxol = paclitaxel.) The Annals of Thoracic Surgery 2001 72, 371-379DOI: (10.1016/S0003-4975(01)02787-4)

Fig 6 Hematoxylin and eosin (H&E) and immunohistochemical staining of tumor tissues harvested 24 hours after completion of the full 4-week course chemotherapy for molecular markers including erbB2, vascular endothelial cell growth factor (VEGF), von Willebrand (vW) factor (staining for endothelial cells to evaluate tumor microvasculature) and activated caspase 3 (only present in apoptotic cells). Representative photomicrographs of tumors treated with phosphate-buffered saline (control), 17-allylamino geldanamycin (17-AAG) (25 mg/kg), paclitaxel (1 mg/kg), or both are shown here. Hematoxylin and eosin: magnification, ×200; immunohistochemical staining: magnification, ×400. The Annals of Thoracic Surgery 2001 72, 371-379DOI: (10.1016/S0003-4975(01)02787-4)