title: Sunitinib inhibits tumor vascularity and growth but does not affect Akt and ERK phosphorylation in xenograft tumors.
abstract: Sunitinib is a multikinase inhibitor approved for use in some human solid malignancies, including renal clear cell and gastrointestinal stromal cancer, and under investigation for many other neoplasias. In many preclinical cancer models sunitinib has shown anti-angiogenic and antitumor effects, acting mainly by inhibiting the activity of pro-angiogenic growth factor receptors. However, a percentage of tumors develop resistance to this treatment. The aim of this study was to identify novel potential molecular targets for the non- responsive tumors. The effects of sunitinib were investigated in xenograft tumors obtained by injecting HEK293 cells into NOD-SCID mice, focusing on the activity of growth-regulating pathways involved in tumorigenesis. During 11 days of oral administration of sunitinib (40 mg/kg/day), the growth of tumors was monitored by measuring the mass volume by a caliper. At the end of the treatment, tumor specimens were histologically examined for microvessel density (MVD) and presence of necrosis, and the phosphorylation of ERK and Akt was analyzed in protein extracts by Western blotting. Moreover, the mRNA levels of VEGF and its receptor genes were measured by quantitative RT-PCR. Treatment with sunitinib elicited a clear reduction of the tumor growth, associated with a reduction of MVD, correlated with an increased number of necrotic cells. In contrast, the levels of phosphorylated Akt and ERK proteins were similar in treated and non-treated animals. The VEGF and VEGFR-1 and 2 transcripts were not affected by sunitinib treatment. In conclusion, these findings confirm the anti-angiogenic action as the major effect of sunitinib against tumor growth. In contrast, other important growth regulatory pathways involved in malignant trans-formation, such as the ERK-MAPK and Akt/mTOR pathways are not affected by such a treatment, suggesting the use of specific inhibitors of these pathways as valid candidates for combinatorial therapies in sunitinib-resistant malignancies.
authors.affiliation: Department of Internal Medicine, University of Perugia, I-06126 Perugia, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Voce
authors.forename: Maria
authors.initials: M
authors.lastname: D'Agostino
authors.forename: Sonia
authors.initials: S
authors.lastname: Moretti
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.forename: Kerry
authors.initials: K
authors.lastname: Rhoden
authors.forename: Filippo
authors.initials: F
authors.lastname: Calcinaro
authors.forename: Giulia
authors.initials: G
authors.lastname: Tamburrano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: Efisio
authors.initials: E
authors.lastname: Puxeddu
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D042501:Angiogenic Proteins / Q000096:biosynthesis; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055806:Microvessels / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D007211:Indoles; D011758:Pyrroles; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077210:Sunitinib