Kinase-addiction and bi-phasic sensitivity-resistance of Bcr-Abl- and Raf-1-expressing cells to imatinib and geldanamycin.
By activating anti-apoptotic factors (e.g., Hsp70, Raf-1, Bcl-xL), Bcr-Abl blocks apoptotic pathways at multiple levels, thus rendering leukemia cells resistant to chemotherapeutic agents such as doxorubicin (DOX). In Bcr-Abl-transfected HL60 (HL/Bcr-Abl) cells, procaspase-9 was increased and partially processed. The Bcr-Abl inhibitor imatinib (Gleevec, STI-571) released the apoptotic stream. Also, HL/Bcr-Abl cells were hyper-sensitive to geldanamycin (GA), which depletes Bcr-Abl and Raf-1. Raf-1 and Bcr-Abl-transfected FDC-P1 hematopoietic cells were selectively sensitive to GA and imatinib, respectively. Remarkably, cell clones with high levels of Bcr-Abl that could not be depleted by GA were relatively resistant to both GA and imatinib. GA and flavopiridol sensitized such resistant cells to imatinib. These data suggest bi-phasic sensitivity to mechanism-based therapeutic agents. Although Bcr-Abl renders cells hyper-sensitive, an excess of Bcr-Abl results in resistance (due to the remaining activity). We discuss therapeutic approaches to overcome bi-phasic resistance to mechanisms-based agents.
Demidenko
Zoya N
ZN
Brander Cancer Research Institute, New York Medical College, Valhalla, New York, USA.
An
Won G
WG
Lee
John T
JT
Romanova
Larisa Y
LY
McCubrey
James A
JA
Blagosklonny
Mikhail V
MV
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D016227:Benzoquinones; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D018922:HL-60 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D047029:Lactams, Macrocyclic; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011809:Quinones / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D016227:Benzoquinones; D005419:Flavonoids; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010879:Piperazines; D010880:Piperidines; D011743:Pyrimidines; D011809:Quinones; C077990:alvocidib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D019908:Proto-Oncogene Proteins c-raf; C001277:geldanamycin