title: Staurosporine analogs promote distinct patterns of process outgrowth and polyploidy in small cell lung carcinoma cells.
abstract: We have recently shown that staurosporine mediates the conversion of small cell lung carcinoma (SCLC) cells into a neuron-like process-bearing phenotype. Here, we have extended these studies to the staurosporine analogs K252a, lestaurtinib, PKC412, stauprimide, and UCN-01 and analyzed their influence on process extension, cell cycle distribution, and induction of polyploidy in four SCLC cell lines. In GLC-2 cells, all compounds provoked extensive process formation with the exception of PKC412 that showed no response. In H1184 cells, process formation was predominantly induced by staurosporine and, to lesser extent, in lestaurtinib-, stauprimide-, and UCN-01-treated cells. In the presence of K252a or PKC412, cells became bipolar and spindle shaped or showed pronounced cell flattening. In GLC-36 and SCLC-24H cells, only cell flattening was detectable. Process formation was reversible upon drug removal as shown for GLC-2 and H1184 cells. Fluorescence-activated cell sorting (FACS) and fluorescence in situ hybridization (FISH) analysis indicated the induction of polyploidy in all staurosporine and in two out of four stauprimide-treated SCLC cell lines. For other staurosporine analogs, polyploidy was observed only in UCN-01-treated GLC-36 cells and in K252a-treated H1184 and GLC-36 cells. The presence of staurosporine or its analogs did not alter the constitutive activation pattern of the canonical Akt/PI3K or MEK/extracellular signal-regulated kinase (ERK)1/2 signaling pathways nor could we detect an influence of stauprimide application on the expression level of the c-Myc oncogene. These data demonstrate that in SCLC cells, albeit a higher substrate specificity, staurosporine analogs can induce staurosporine-comparable effects.
authors.affiliation: Department of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Hichem
authors.initials: H
authors.lastname: Gallala
authors.forename: Jochen
authors.initials: J
authors.lastname: Winter
authors.forename: Nadine
authors.initials: N
authors.lastname: Veit
authors.forename: Michael
authors.initials: M
authors.lastname: Nowak
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.forename: Cornelius
authors.initials: C
authors.lastname: Courts
authors.forename: Dominik
authors.initials: D
authors.lastname: Kraus
authors.forename: Viktor
authors.initials: V
authors.lastname: Janzen
authors.forename: Rainer
authors.initials: R
authors.lastname: Probstmeier
mesh_terms: D002227:Carbazoles / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005663:Furans; D006801:Humans; D026121:Indole Alkaloids / Q000008:administration & dosage; D011123:Polyploidy; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D019311:Staurosporine / Q000008:administration & dosage* / Q000031:analogs & derivatives
chemical_list: D002227:Carbazoles; D005663:Furans; D026121:Indole Alkaloids; C049985:staurosporine aglycone; C119379:lestaurtinib; D019311:Staurosporine; C059539:midostaurin