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Therapeutic effect of imatinib improved with addition of chloroquine
April 14, 2009Autophagy, a process that helps leukemia cells evade cell death, appears to be an effect of imatinib treatment
(PHILADELPHIA) 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."
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."
Thomas Jefferson University
Autophagy Current Events and Autophagy News RSSInhibitor of heat shock protein is a potential anticancer drug, Penn study finds
Like yoga for office drones, cells do have coping strategies for stress. Heat, lack of nutrients, oxygen radicals - all can wreak havoc on the delicate internal components of a cell, potentially damaging it beyond repair.
HIV uses autophagy for its own means
Not satisfied with simply thwarting its host's defensive maneuvers, HIV actually twists one to its advantage, based on new findings from Kyei et al. in the July 27, 2009 issue of the Journal of Cell Biology (www.jcb.org). Vojo Deretic and colleagues suggest that autophagy-a stress response process-helps HIV to proliferate and that conversely, blocking autophagy lessens HIV production.
Waste disposal protein is mechanism behind cancer tumor suppression
"Taking out the trash" takes on a whole new meaning, as investigators at The Cancer Institute of New Jersey (CINJ) and Rutgers, The State University of New Jersey, have discovered that a waste disposal protein is the key to cancer tumor suppression in a process known as autophagy.
Scientists advance safety of nanotechnology
Scientists have identified for the first time a mechanism by which nanoparticles cause lung damage and have demonstrated that it can be combated by blocking the process involved, taking a step toward addressing the growing concerns over the safety of nanotechnology.
Muscle atrophy through thick but not thin
During desperate times, such as fasting, or muscle wasting that afflicts cancer or AIDS patients, the body cannibalizes itself, atrophying and breaking down skeletal muscle proteins to liberate amino acids.
Enhancing the effects of the drug used to treat chronic myeloid leukemia
Individuals with chronic myeloid leukemia (CML) are first treated with a drug known as imatinib mesylate. Although very effective, as the disease progresses it often becomes resistant to the drug.
TB breakthrough could lead to stronger vaccine
A breakthrough strategy to improve the effectiveness of the only tuberculosis vaccine approved for humans provided superior protection against the deadly disease in a pre-clinical test, report scientists at The University of Texas Health Science Center at Houston in Nature Medicine's Advance Online Publication March 1.
Self-digestion as a means of survival
In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process - known as autophagy - takes place in special organelles called autophagosomes.
Helicobacter pylori can multiply in autophagic vesicles
Helicobacter pylori, a Gram-negative, flagellated, microaerophilic bacterium, can selectively colonize in the human stomach. Its infection is widespread throughout the world, and is present in about 50% of the global human population with 80% in developing countries and 20-50% in industrialized countries.
Toxicity mechanism identified for Parkinson's disease
Neurologists have observed for decades that Lewy bodies, clumps of aggregated proteins inside cells, appear in the brains of patients with Parkinson's disease and other neurodegenerative diseases.
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