Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha.
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.
Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Beirut, Lebanon.
Rabab M
RM
El Eit
Ahmad N
AN
Iskandarani
Jessica L
JL
Saliba
Mark N
MN
Jabbour
Rami A
RA
Mahfouz
Nizar M A
NM
Bitar
Hanadi R El
HR
Ayoubi
Ghazi S
GS
Zaatari
Francois-Xavier
FX
Mahon
Hugues B
HB
De Thé
Ali A
AA
Bazarbachi
Rihab R
RR
Nasr
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010087:Oxides / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011379:Prognosis; D011743:Pyrimidines / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000998:Antiviral Agents; D001152:Arsenicals; D001549:Benzamides; D016898:Interferon-alpha; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000077237:Arsenic Trioxide
CML mouse model; arsenic trioxide; chronic myeloid leukemia; imatinib; interferon alpha; leukemia initiating cells