Therapeutic Effect of Imatinib Improved with Addition of Chloroquine
The therapeutic effects of the
blockbuster leukemia drug imatinib may be enhanced when given along with a drug
that inhibits a cell process called autophagy, researchers from the Kimmel Cancer Center at Jefferson
reported in the Journal of Clinical Investigation.
The cell-death effect of imatinib
(Gleevec) was potentiated when chloroquine, an autophagy inhibitor, was given
with imatinib for the in vitro treatment of chronic myeloid leukemia (CML) cells
including the CML stem cells, according to Bruno Calabretta, M.D., Ph.D.,
professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson
University.
Autophagy is a process that allows cells
to adapt to environmental stresses, and enables drug-treated CML cells to escape
cell death. Imatinib is a tyrosine kinase inhibitor that suppresses
proliferation and induces death of the malignant cells that cause CML. However,
additional effects of the drug have not been studied in detail, according to Dr.
Calabretta.
In this study, Dr. Calabretta’s team,
along with Dr. Paolo Salomoni’s team from the MRC Toxicology Unit at the
University of Leicester in the United Kingdom, found that imatinib induces
autophagy in CML stem cells that overexpress a protein called
p210BCR/ABL. Stem cells that express this protein have been
historically resistant to imatinib and also to second-generation tyrosine kinase
inhibitors, including dasatinib, nilotinib and bosutinib.
The autophagy process allows stem cells
to survive treatment with imatinib, and continue to survive. The researchers
used chloroquine to see if it would have an effect on imatinib treatment. The
dual treatment with imatinib and chloroquine eliminated most CML stem cells.
Also, imatinib-induced cell death was significantly increased in mice inoculated
with p210BCR/ABL-expressing cells.
“Imatinib’s primary effect is inhibiting
the proliferation of CML cells, but the frequency of resistance increases in
advanced stages of the disease,” Dr. Calabretta said. “There is a need to
develop new therapeutic approaches that, in combination with tyrosine kinase
inhibitors, eliminate CML stem cells that escape imatinib treatment. We show
that imatinib induces autophagy, which enables these cells to survive and
eventually resume proliferation. We also show that chloroquine, an autophagy
inhibitor, combined with imatinib actually appears to potentiate
imatinib-induced cell death.”
Media Only Contact:
Emily Shafer
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 4/15/2009