~ Forskolin May Suppress Leukemia Progression

In the November 2005 issue of the journal Cancer Cell, scientists from Ohio State University identified a new pathway of chronic myelogenous leukemia (CML) progression. Chronic myelogenous leukemia develops when two chromosomes erroneously exchange genetic material during cell division, creating a new gene that produces the cancer-causing enzyme Bcr-Abl. Bcr-Abl turns on cell growth signals, which, when unchecked by phosphatases, result in the abnormal production of white blood cells. The disease is currently treated with the so-called wonder-drug Gleevec which blocks Bcr-Abl activity, but a large number of patients develop resistance to the treatment.

Until now, it was unknown how the disease progressed through its well defined stages. Danilo Perrotti, who is an assistant professor in the department of molecular virology, immunology and medical genetics at Ohio State University and colleagues discovered that Bcr-Abl stimulates the protein SET which inhibits the tumor suppressor phosphatase PP2A. The team discovered that in chronic myelogenous leukemia, PP2A suppression only occurs in the final, acute stage of the disease.

Acting on previous research findings that showed that forskolin, extracted from the root of the ornamental plant coleus forskohlii, could restore PP2A function, the extract was tested on normal, Gleevec-sensitive and Gleevec-resistant human CML cells. The researchers found that forskolin restored normal PP2A function, while reducing the cancer cells' ability to grow by up to 90 percent. It also induced cancer cell death and differentiation while failing to effect normal cells. When forskolin was tested on mice, withdrawal of the compound resulted in the death of some of the animals while others showed signs of Bcr-Abl activity, but when forskolin was readministered, Bcr-Abl was blocked.

Dr Perotti commented, "We believe these are significant findings. We have uncovered a key process that underlies progression in CML and identified an agent that can block it. We also have shown that forskolin can reinstate normal cell functioning, even in Gleevec-resistant cells that do not respond to any treatment currently available."
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