PT  - JOURNAL ARTICLE
AU  - R S Chapman
AU  - A D Whetton
AU  - C M Chresta
AU  - C Dive
TI  - Characterization of drug resistance mediated via the suppression of apoptosis by Abelson protein tyrosine kinase.
DP  - 1995 Aug 01
TA  - Molecular Pharmacology
PG  - 334--343
VI  - 48
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/48/2/334.short
4100  - http://molpharm.aspetjournals.org/content/48/2/334.full
SO  - Mol Pharmacol1995 Aug 01; 48
AB  - 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.