Therapeutic effect of imatinib improved with addition of chloroquine

Apr 13, 2009

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 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 that escape imatinib . 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."

Source: Thomas Jefferson University (news : web)

Explore further: Docs face challenges treating HPV oropharyngeal CA patients

add to favorites email to friend print save as pdf

Related Stories

Can cancer drugs combine forces?

Aug 16, 2007

Individuals with chronic myeloid leukemia (CML) are treated first with a drug known as imatinib (Gleevec), which targets the protein known to cause the cancer (BCR-ABL). If their disease returns, because BCR-ABL mutants emerge ...

Recommended for you

Decoding the emergence of metastatic cancer stem cells

14 hours ago

In the first study of its kind, Rice University researchers have mapped how information flows through the genetic circuits that cause cancer cells to become metastatic. The research reveals a common pattern ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.