title: KIF11 inhibition for glioblastoma treatment: reason to hope or a struggle with the brain?
abstract: BACKGROUND
  Glioblastomas (GBM) are typically comprised of morphologically diverse cells. Despite current advances in therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Unfortunately, most patients die within 2 years of diagnosis of their disease. Molecular abnormalities vary among individual patients and also within each tumor. Indeed, one of the distinguishing features of GBM is its marked genetic heterogeneity. Due to the brain location of the tumor, the potential target inhibition for anticancer therapy must exhibit a manageable neurotoxicity profile in the concentration range in which the compounds show anti-proliferative activity.Kinesin KIF11 inhibition by small molecules such as Monastrol or Ispinesib is currently under investigation in the field of malignant tumors. In the current study we have assessed the relevance of the anti-mitotic Kinesin-like protein KIF11 in human GBM cell-lines.
  
  
  RESULTS
  In this study the target was validated using a set of well characterised and potentially specific small molecule inhibitors of KIF11: an ispinesib analog, Monastrol, a Merck compound and 3 simplified derivatives of the Merck compound. Following an in silico selection, those compounds predicted to bear a favorable BBB permeation profile were assessed for their phenotypic effect on cell lines derived both from primary (U87MG) as well as treated (DBTRG-05-MG) glioblastomas. For some compounds, these data could be compared to their effect on normal human astrocytes, as well as their neurotoxicity on primary rat cortical neurons. The ispinesib analogue 1 showed an anti-proliferative effect on GBM cell lines by blocking them in the G2/M phase in a concentration range which was shown to be harmless to primary rat cortical neurons. Furthermore, ispinesib analog increased caspase 3/7-induced apoptosis in U87MG cells.
  
  
  CONCLUSIONS
  In the area of cell cycle inhibition, KIF11 is critical for proper spindle assembly and represents an attractive anticancer target. Our results suggest that KIF11 inhibitors, when able to permeate the blood-brain-barrier, could represent an interesting class of anticancer drugs with low neurotoxic effects in the treatment of brain tumors.
authors: SienaBiotech S,P,A, Discovery Research, Strada di Petriccio Belriguardo 35, 53100 Siena, Italy. svalensin@sienabiotech.it
authors: Silvia
authors: S
authors: Valensin
authors: Chiara
authors: C
authors: Ghiron
authors: Claudia
authors: C
authors: Lamanna
authors: Andreas
authors: A
authors: Kremer
authors: Marco
authors: M
authors: Rossi
authors: Pietro
authors: P
authors: Ferruzzi
authors: Marco
authors: M
authors: Nievo
authors: Annette
authors: A
authors: Bakker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D008941:Spindle Apparatus / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C470243:KIF11 protein, human; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins