title: Differential impact of fibroblasts on the efficient cell death of lung cancer cells induced by paclitaxel and cisplatin.
abstract: The efficient treatment of lung carcinomas with chemotherapeutics still poses a challenge for anti-cancer therapy. Since stromal cells of the tumor may alter the responsiveness of tumor cells to chemotherapeutics, we studied the impact of lung fibroblasts (WI-38) on the chemotherapy-induced death of non-small cell lung carcinoma cells (H358). Conditioned medium from WI-38 fibroblasts impaired the H358 cell death induced by paclitaxel but not by cisplatin. Comparable results were observed when culturing H358 cells in conditioned medium from primary tumor fibroblasts or co-culturing H358 cells with fibroblasts. This anti-apoptotic effect induced by paracrine signaling from fibroblasts was associated with less necrosis (membrane leakage, mitochondrial dysfunction) and apoptosis (outer membrane phosphatidylserine exposure, pycnotic nuclei, nuclear translocation of the apoptosis-inducing factor from mitochondria, caspase-9 and -3/-7 activation) in response to paclitaxel but not cisplatin. Additionally, we demonstrated that WI-38 fibroblasts mediate activation of both extracellular signal-regulated kinases (Erk) 1/2 and Akt kinase in H358 cells. Subsequent application of specific inhibitors revealed that the paclitaxel-induced cell death is highly impaired by active Erk1/2 and Akt, whereas the cisplatin-induced cell death is independent of both kinases. Pro-apoptotic Bcl-2 family proteins such as Bim cannot explain the differential impact of fibroblasts on the H358 cell death induced by paclitaxel compared with cisplatin. Our data support the preferential use of the cisplatin-based lung carcinoma therapy, because the cell death-inducing efficiency of cisplatin is not impaired by stromal fibroblasts.
authors.affiliation: Department of Cardio-thoracic Surgery, University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. babett.bartling@medizin.uni-halle.de
authors.forename: Babett
authors.initials: B
authors.lastname: Bartling
authors.forename: Hans-Stefan
authors.initials: HS
authors.lastname: Hofmann
authors.forename: Rolf-Edgar
authors.initials: RE
authors.lastname: Silber
authors.forename: Andreas
authors.initials: A
authors.lastname: Simm
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D017077:Culture Media, Conditioned; D017239:Paclitaxel; D002945:Cisplatin