ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines.
BACKGROUND
Therapeutic approaches to gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still not satisfactory. A new direction in treatment options could be the novel aurora kinase inhibitor ZM447439, which was previously reported to interfere with the mitotic spindle integrity checkpoint and chromosome segregation, but does not interfere with other kinases when used up to 5 muM.


METHODS
We evaluated the antineoplastic effects of ZM447439 on growth and apoptosis of the GEP-NET cell lines BON, QGP-1 and MIP-101, representing the different malignant tumor types, using standard cell biological tests as crystal violet assays, caspase activation, DNA fragmentation and cell cycle analysis.


RESULTS
ZM447439 dose-dependently inhibited proliferation of all three cell lines with IC(50) values in the nanomolar to low micromolar range. Moreover, aurora kinase inhibition by ZM447439 potently induced apoptosis, which was accompanied by DNA fragmentation and caspase 3 and 7 activation. Furthermore, we observed cell cycle arrest at G(0)/G(1) phase as well as a block in G(2)/M transition. In addition, combined treatment with the chemotherapeutic agents streptozocin and cisplatin augmented significantly the antiproliferative effects of those agents.


CONCLUSIONS
Aurora kinase inhibition by ZM447439 seems to be a promising new therapeutic approach in GEP-NETs, which should be evaluated in further clinical trials.
Georgieva
I
I
Gastroenterologie/Infektiologie/Rheumatologie, Medizinische Klinik I, Hämatologie/Onkologie und Transfusionmedizin, Medizinische Klinik III, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Koychev
D
D
Wang
Y
Y
Holstein
J
J
Hopfenmüller
W
W
Zeitz
M
M
Grabowski
P
P
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013311:Streptozocin / Q000494:pharmacology; D000077022:Survivin; D016708:Synaptophysin / Q000378:metabolism
C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; C107489:BIRC5 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D011799:Quinazolines; D000077022:Survivin; D016708:Synaptophysin; D013004:Somatostatin; D013311:Streptozocin; D004317:Doxorubicin; C517782:pasireotide; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin; D015282:Octreotide; D005472:Fluorouracil