Scientists in the U.S. believe they have identified a new pathway in the progression of chronic myelogenous leukemia (CML).
They have also discovered that an extract from the root of a common ornamental plant can suppress the process.
The exciting new extract is forskolin, which comes from the root of the plant coleus forskohlii, a native of India that is used in the U.S. as an ornamental plant.
Their findings may suggest new treatment options for the estimated 4,600 people in the United States who are expected to develop CML this year, in particular those in the advanced stages of the disease, or those who become resistant to the commonly used drug Gleevec.
Early results on CML patient cells both in culture and in mice have apparently shown that forskolin reduced the cancer cells' ability to grow by up to 90 percent.
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, says the findings are significant.
He believes they have uncovered a key process that underlies progression in CML and identified an agent that can block it.
They have also shown, he says, that forskolin can reinstate normal cell functioning, even in Gleevec-resistant cells that do not respond to any current treatment.
CML arises when two chromosomes mistakenly exchange genetic material during cell division.
This action creates a new, fused gene that produces a cancer-causing enzyme called Bcr-Abl.
This enzyme 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.
Apparently patients with the earliest form of the disease may not even be aware they are sick.
If discovered early the disease 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 developed resistance to the drug.
In these patients, white blood cells continue to proliferate and 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.
Although doctors easily recognise the signs and symptoms of the different stages of CML, until now, they have had few clues about what actually causes the disease to progress.
Perrotti says his studies show that it may be due to the increased activity of Bcr-Abl itself.
Perrotti discovered by extensive chemical and genetic tests, conducted in collaboration with an international group of researchers, that Bcr-Abl stimulates a protein called SET, which, in turn, inhibits the phosphatase PP2A.
When PP2A isn't working properly, cancer cells are free to grow and spread.
It seems that while PP2A suppression occurs in other forms of cancer, Perrotti said their tests reveal that in CML, it only occurs in the blast crisis, and in the initial, chronic phase of the disease.
Perrotti remembered from earlier studies that forskolin could restore PP2A function; however although 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.
In their research Perrotti and his 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.
In the meantime it had no adverse effects upon normal cells.
The team found that when leukemic mice which had been treated with forskolin then stopped getting the treatment, some died of leukemia and others showed evidence of Bcr-Abl activity.
But once the forskolin treatment was resumed, even weeks after the initial treatment had stopped, Bcr-Abl activity was blocked and normal cell functioning was reinstated.
Perrotti says forskolin may well be an additional or potential treatment for patients with CML who have already advanced to the blast phase, but more pre-clinical and pharmacologic studies need to be done to assess the therapeutic relevance of forskolin in patients with leukemia.
The research is published in the November issue of Cancer Cell.