Synergistic activity of nilotinib and established chemotherapeutic drugs in imatinib-sensitive and -resistant BCR-ABL-positive cells

• Verfasst von: Radujković, Aleksandar [VerfasserIn]
• Verfasst von: Fruehauf, Stefan [VerfasserIn]
• Verfasst von: Zeller, W. Jens [VerfasserIn]
• Verfasst von: Ho, Anthony Dick [VerfasserIn]
• Verfasst von: Topaly, Julian [VerfasserIn]
• Titel: Synergistic activity of nilotinib and established chemotherapeutic drugs in imatinib-sensitive and -resistant BCR-ABL-positive cells
• Verf.angabe: Aleksandar Radujkovic, Stefan Fruehauf, W. Jens Zeller, Anthony D. Ho, Julian Topaly
• Jahr: 2010
• Umfang: 10 S.
• Fussnoten: Online veröffentlicht: 28. Oktober 2009 ; Gesehen am 09.05.2023
• Titel Quelle: Enthalten in: Cancer chemotherapy and pharmacology
• Ort Quelle: Berlin : Springer, 1978
• Jahr Quelle: 2010
• Band/Heft Quelle: 66(2010), 2, Seite 255-264
• ISSN Quelle: 1432-0843
• DOI: doi:10.1007/s00280-009-1158-7
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: BCR-ABL
• Sach-SW: Combination treatment
• Sach-SW: Imatinib resistance
• Sach-SW: Nilotinib
• Sach-SW: Synergism
• K10plus-PPN: 1844879313

Abstract

We investigated various combination treatment regimens employing nilotinib with established chemotherapeutic agents (daunorubicin, mitoxantrone, etoposide and cytarabine) in imatinib-sensitive and -resistant BCR-ABL-positive cells. Mitoxantrone or cytarabine showed synergism (CI < 1) in combination with nilotinib in imatinib-sensitive LAMA84 cells, whereas in imatinib-resistant LAMA84-R cells synergistic effects could be assessed for daunorubicin, mitoxantrone and etoposide when combined with nilotinib. In both imatinib-sensitive and -resistant K562 cells daunorubicin, mitoxantrone and etoposide demonstrated synergism in combination with nilotinib. Moreover, both daunorubicin and mitoxantrone led to synergistic antiproliferative effects when combined with nilotinib in imatinib-resistant Ba/F3 cells carrying point mutations in the ABL TK domain (E255K, E255V and T315I). Annexin V/propidium iodide staining revealed a significant enhancement of nilotinib-induced apoptosis in imatinib-resistant Ba/F3T315I and LAMA84-R cells upon combination with daunorubicin and mitoxantrone, respectively. Our results demonstrate the efficacy of combination treatment regimens employing nilotinib and established chemotherapeutic agents in improving antileukemic effects in imatinib-sensitive and imatinib-resistant cells. This may be the foundation for further study on the potential of the applied combinations in a clinical setting.