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Forskolin may be effective in Imatinib-resistant patients in chronic myelogenous leukaemia

Researchers 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 journal Cancer Cell, may yield new treatment options for the estimated 4,600 people in the United States who are expected to develop chronic myelogenous leukemia this year – especially those with advanced disease, or those who become resistant to the drug Imatinib ( Gleevec/ Glivec ).

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, at OSU Comprehensive Cancer Center. “ We have uncovered a key process that underlies progression in chronic myelogenous leukemia and identified an agent that can block it. We also have shown that forskolin can reinstate normal cell functioning, even in Imatinib-resistant cells that do not respond to any treatment currently available.”

Chronic myelogenous leukemia 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 chronic myelogenous leukaemia.

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 Imatinib, which puts the brakes on Bcr-Abl activity.
FDA ( Food and Drug Administration ) approved Gleevec as a treatment for chronic myelogenous leukaemia.

But since then, a significant minority of patients who initially responded well to Imatinib 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 chronic myelogenous leukemia , 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 chronic myelogenous leukemia, 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 bronchodilator and vasodilator 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, Imatinib-sensitive and Imatinib-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.

Source: Ohio State University, 2005