title: STI571 and morpholine derivative of doxorubicin collaborate in inhibition of K562 cell proliferation by inducing differentiation and mitochondrial pathway of apoptosis.
abstract: Differentiation therapy is considered as a supplementary approach to the currently applied treatments for leukemia. We have previously shown that a morpholine derivative of doxorubicin (DOXM) appeared to be a more efficient inducer of erythroid differentiation of K562 cells than the parent drug [Czyz, M., Szulawska, A., Bednarek, A.K., Duchler, M., 2005. Effects of anthracycline derivatives on human leukemia K562 cell growth and differentiation. Biochem. Pharmacol. 70, 1431-1442.; Szulawska, A., Arkusinska, J., Czyz, M., 2007. Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives. Biochem. Pharmacol. 73, 175-184.]. In the current study we used this compound in combination with STI571, a front-line drug in therapy of chronic myelogenous leukemia (CML), to evaluate possible benefits of the combined treatment on the cellular level. Using K562 cells, we analyzed the response of CML cells to low concentrations of DOXM when Bcr-Abl activity was reduced to various levels by its specific inhibitor, STI571. Differentiation was significantly enhanced with the combination of 150 nM STI571 and 100 nM DOXM as compared to the levels obtained with either drug alone. A higher concentration of STI571 was required to diminish Bcr-Abl activity to the level which was sufficient to stimulate apoptotic cell death pathway in K562. Apoptosis induced by 250 nM STI571 was markedly enhanced by DOXM in the combined treatment. Mitochondrial transmembrane potential dissipation and translocation of phosphatydylserine to the outer plasma membrane were increased by 50%. Our results clearly indicate that differentiation and apoptosis, both reducing cellular proliferation, could be substantially enhanced by the combined treatment. We provide experimental evidence implicating that the diversification of cellular effects obtained in the combined treatment employing non-toxic approaches to enhance efficacy of STI571 might be considered as an alternative therapeutic strategy against CML, especially for apoptosis-reluctant cells.
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, Lodz, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Jakubowska
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wasowska-Lukawska
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Czyz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004347:Drug Interactions; D015672:Erythroid Precursor Cells / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009025:Morpholines; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000068877:Imatinib Mesylate