Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha

Abstract

Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction=transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic=IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control.

ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model

“…Experiments were approved by the Institutional Animal Care and use Committee of the American University of Beirut. The murine bone marrow retroviral transduction/transplantation model was used as described . Briefly, Plat‐E cells were transfected by the retroviral expressing vector MIGp210 BCR‐ABL .…”

EAPB0503, a novel imidazoquinoxaline derivative, inhibits growth and induces apoptosis in chronic myeloid leukemia cells

“…After the addition of 0.7 mol/l b-mercaptoethanol, an equal amount of total cell lysate (50 mg) was then loaded on a 10% SDS-polyacrylamide gel electrophoresis gel and transferred onto nitrocellulose membranes. Membranes were blocked in 5% fat-free milk and probed against the following antibodies: poly ADP-ribose polymerase (PARP) (Cell Signaling Technologies), mouse monoclonal cAbl (Santa Cruz Technologies, Santa Cruz, California, USA), and mouse monoclonal horseradish peroxidase (HRP)-conjugated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Abnova Corporation, Taipei, Taiwan) [20]. Membranes were then incubated with the appropriate HRP-conjugated secondary antibodies, proteins were detected by chemoluminescence using the luminol detection kit (Santa Cruz Technologies), and autoradiographs were analyzed by densitometric analysis using the ImageJ software (National Institutes of Health, Bethesda, Maryland, USA).…”

“…Seventy-two hours after treatment, control and treated cells were harvested and analyzed by TUNEL according to the manufacturer's instructions (Roche Applied Science) and as described previously [20]. The positive control for the assay was obtained after digestion of untreated cellular DNA by recombinant DNase I enzyme.…”

Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem, Progenitor and Stromal Cell Interplay

“…However, it is still unclear whether Shh inhibition leads to CML eradication without harming normal HSC survival and self-renewal [147-152]. Several strategies to target CML LSCs and/or CML-BC GMPs with HDAC [153], Bcl-xL/BCL2/MCL1 [104, 154, 155], mTOR [156], PML [157, 158], Alox-5 [159, 160], autophagy and proteasome inhibitors [161, 162] showed promising results in preclinical settings and are currently under clinical investigation [23]. Moreover, the regulation of LSC behavior seems to also involve other druggable factors ( e.g.…”