Characterization of drug resistance mediated via the suppression of apoptosis by Abelson protein tyrosine kinase.
Constitutive activation of the Abelson (Abl) protein tyrosine kinase (PTK) is a causative event in chronic myeloid leukemia, where intense chemotherapy currently fails to eradicate the leukemic clone. Using a mouse mast cell line (IC.DP), we previously showed that v-Abl PTK induced resistance to the anti-cancer drugs melphalan and hydroxyurea by the suppression of apoptosis. Here, using this cell line, we demonstrate by alkaline elution that v-Abl PTK did not affect the levels of DNA damage induced by either drug. This confirms that v-Abl PTK acts downstream of the drug-target interaction to prevent the coupling of drug-induced damage to the apoptotic pathway. Although Abl PTK- and interleukin-3 (IL-3)-stimulated signaling events share common signaling pathways, a similar level of drug resistance was not provided by IL-3, implying that Abl PTK does not merely mimic an IL-3 survival signaling pathway. Previously we demonstrated translocation of protein kinase C-beta II stimulated by activation of Abl PTK. Drug sensitivity was restored in cells with active v-Abl PTK by simultaneous addition of calphostin C, an inhibitor of protein kinase C, suggesting a role for protein kinase C in the suppression of drug-induced apoptosis by v-Abl PTK. One novel strategy for the treatment of chronic myeloid leukemia could therefore include the use of a downstream modifier of the Abl PTK-mediated survival signaling pathway to render leukemic cells more sensitive to a second drug, such as a cytotoxic agent.
Chapman
R S
RS
Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
Whetton
A D
AD
Chresta
C M
CM
Dive
C
C
D000011:Abelson murine leukemia virus / Q000201:enzymology*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004351:Drug Resistance; D006918:Hydroxyurea / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
D007377:Interleukin-3; D009281:Naphthalenes; D004247:DNA; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C058819:calphostin C; D008558:Melphalan; D006918:Hydroxyurea