Scientists here have identified a new pathway in the progression of chronic myelogenous leukemia (CML). They also discovered that an extract from the root of a common ornamental plant can suppress the process.

The findings, appearing in the November issue of Cancer Cell, may yield new treatment options for the estimated 4,600 people in the United States who are expected to develop CML this year - especially those with advanced disease, or those who become resistant to the drug Gleevec.

The promising new extract is forskolin, which comes from the root of the plant coleus forskohlii, a native of India that is used in the United States as an ornamental plant.

Early results on CML patient cells both in culture and in mice showed that forskolin reduced the cancer cells' ability to grow by up to 90 percent.

"We believe these are significant findings," said Danilo Perrotti, a member of the OSU Comprehensive Cancer Center 's Molecular Biology and Cancer Genetics Program and an assistant professor in the department of molecular virology, immunology and medical genetics. "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."

CML arises when two chromosomes - 9 and 22 - mistakenly exchange genetic material during cell division. The translocation creates a new, fused gene (called BCR-ABL), that produces a cancer-causing enzyme called Bcr-Abl. Bcr-Abl permanently "turns on" cell growth signals that are normally held in check by molecules called phosphatases, and the result is the uncontrolled production of white blood cells, the hallmark of CML.

Patients with the earliest form of the disease - called the chronic phase - may not even be aware they are sick. If the disease is discovered early, it almost always responds to the drug Gleevec, which puts the brakes on Bcr-Abl activity. The Food and Drug Administration (FDA) approved Gleevec as a treatment for CML about five years ago and it was initially hailed as the first "wonder drug" for cancer.

But since then, a significant minority of patients who initially responded well to Gleevec have acquired additional mutations and developed resistance to the drug. In these patients, white blood cells continue to proliferate. If left unchecked, it leads to the final, acute stage, called the blast crisis, where immature white blood cells infiltrate the blood and the bone marrow.

Clinicians are well-versed in the signs and symptoms of the different stages of CML, but until now, they have had few clues about what actually causes the disease to progress.

Perrotti said his studies show that it may be due to the increased activity of Bcr-Abl itself.

Through extensive chemical and genetic tests conducted in collaboration with an international group of researchers, Perrotti determined that Bcr-Abl stimulates a protein called SET, which, in turn, inhibits the phosphatase PP2A. PP2A is important because it acts like a tumor suppressor, applying the brakes to growth signals stuck in the "on" position. When PP2A isn't working properly, cancer cells are free to grow and spread.

While PP2A suppression occurs in other forms of cancer, Perrotti said their tests reveal that in CML, it only occurs in the blast crisis, not in the chronic phase of the disease.

From earlier studies, Perrotti recalled that forskolin could restore PP2A function. Even though forskolin is currently used in Japan as a broncho- and vaso-dilator and has been tested and found safe in clinical trials in Austria among patients with asthma, it has not been approved by the FDA for use in the United States .

Perrotti and his research team tested the effects of forskolin on normal, Gleevec -sensitive and Gleevec-resistant CML cells, and discovered that the extract restored normal PP2A function, reduced the cancer cells' ability to grow by up to 90 percent and induced leukemic cell death and differentiation. It had no adverse effects upon normal cells.

Interestingly, when leukemic mice treated with forskolin stopped getting the treatment, some died of leukemia and others showed evidence of Bcr-Abl activity. But starting treatment again with forskolin - even weeks after initial treatment had stopped - blocked Bcr-Abl activity and reinstated normal cell functioning.

Is forskolin, then, a potential treatment for patients with CML who have already advanced to the blast phase? It may well be, but Perrotti says additional pre-clinical and pharmacologic studies must still be conducted to further assess the therapeutic relevance of forskolin in patients with leukemia.

Several agencies and organizations supported the research, including the National Cancer Institute, The U.S. Army CML Research Program, the Elsa Pardee Foundation for Cancer Research, the Lauri Strauss Leukemia Research Foundation, the Leukemia Clinical Research Foundation and Fonds de la Recherche en Sante du Quebec.

Michelle Gailiun
Gailiun.1osu.edu
Ohio State University
researchnews.osu.edu

View drug information on Gleevec.