What is curcumin and what sparked the thought that it could help in combating the progression of cancer?
An important point about this work is that the research into curcumin was conducted following a discovery about mesothelioma, rather than being the primary endpoint of the study.
The basic premise of this particular study was to use curcumin as a means of increasing a specific protein within the cell called PIAS3 (protein inhibitor of activated STAT3).
We used curcumin, in particular, because published literature has shown that, amongst the many things that curcumin can do, it can increase the amount of intracellular PIAS3 within cancer cells.
We then capitalized on that information by using it in our study of curcumin in mesothelioma.
Why did your research focus on mesothelioma?
I'm a thoracic oncologist, so I treat patients with thoracic malignancies, with lung cancer of course being the predominant cancer within the thorax.
There have been many advances in lung cancer, yet very little advances in the treatment of mesothelioma (aside from some chemotherapy that was developed almost a decade ago). So, we felt there was a very big and un-met need in terms of research.
We were interested in mesothelioma not only because it lies within my area of expertise, but because when we looked for PIAS3 across many types of cancer, we noticed that mesothelioma is associated with the lowest levels of PIAS3.
In the current work, we demonstrated that, compared with other cancers, mesothelioma expresses very little PIAS3, which led us to question whether this low PIAS3 level may be responsible for activation of a very well-known pathway in cancer termed the STAT3 pathway.
Is mesothelioma always caused by asbestos exposure?
The answer to that is that while the majority of cases are, definitely not all are. At least from a historical standpoint, there are cases where patients do not report exposure to asbestos or at least not a known exposure to asbestos.
In addition, there are certain areas of the world, such as certain areas in Turkey, where mesothelioma occurs without exposure to asbestos and is thought to possibly be caused by certain minerals in the ground.
Please can you explain what is known about signal transducer and activator of transcription 3 (STAT3) and protein inhibitor of activated STAT3 (PIAS3)?
STAT3 is a critical protein because it is a key intracellular signalling pathway. Signalling pathways are critical for transmitting messages from the surface of cells to the DNA inside the nucleus, so they are needed to convey messages from the cell’s external environment to its internal one.
These signalling pathways usually cause the growth of cells. When STAT3 is activated, cancer cells grow and can also resist death. This activation of STAT3 has been demonstrated in a number of cancers, including in mesothelioma, however, what was previously unknown is why STAT3 is activated in mesothelioma.
Our research has demonstrated that PIAS3 acts as a natural inhibitor of STAT3. To understand this, you can think of STAT3 as the accelerator increasing the speed of a car and PIAS3 as the brake used to stop STAT3 getting out of control.
When we found activated STAT3 in mesothelioma, we wondered whether it is activated specifically because the level of PIAS3 (its natural breaking mechanism) is very low in mesothelioma, compared with other cancers.
Indeed, when you look within mesothelioma cancer cells, that's exactly what you find – evidence of low PIAS3 in mesothelioma cell lines that have activated STAT3.
How did you examine the effects of curcumin?
Currently, there are no good anti-STAT3 drugs out there and there's a lot of research going on by various companies who are trying to find STAT3 inhibitors.
Once we knew that the natural inhibitor of STAT3, PIAS3, is low in mesothelioma, we then asked ourselves what we could do to increase PIAS3.
As previous researchers had already demonstrated that curcumin can increase PIAS3, we used curcumin to increase the PIAS3 levels in mesothelioma cancer cells.
When we exposed these cells to low levels of curcumin, we saw an increase in the intracellular levels of PIAS3. Furthermore, when we increased PIAS3, the activation of STAT3 decreased, and, in turn, the cancer cells started growing much more slowly or stopped growing altogether. So, curcumin affects mesothelioma cells by increasing the intracellular PIAS3 and therefore decreasing the STAT3 activation and cancer cell growth.
What impact do you think this research will have and what are your further research plans?
I think the impact it will have, first and foremost, is to provide insight into the biology of mesothelioma. It will help people understand that STAT3 activation is critical and that we must work on ways to inhibit it. This could be achieved through either direct STAT3 inhibitors or indirect ones – inhibitors that will do something else and then decrease STAT3.
Our work is going to be focused on finding ways to inhibit STAT3 and in particular, how to increase PIAS3. For example, during this research we also used a peptide, developed by a group in Germany, which comes from PIAS3. They took a small segment from the whole PIAS3 protein and developed what we call a peptide.
They gave us that peptide to test on our mesothelioma cells. Even that little segment of PIAS3 was capable of stopping STAT3. We want to find ways to use PIAS3, either by increasing it naturally or by using segments of PIAS3 to see if it will inhibit cancer cell growth.
Importantly, curcumin is generally thought to have a poor bioavailability, meaning that if you eat it, you're not going to absorb much of it. It is therefore very possible that curcumin may not have a direct effect on mesothelioma, partly because it just won’t be able to reach the cancer.
However, research is going on around the world to develop curcumin analogues that have a good bioavailability. The key component here is going to be finding curcumin analogues that will be safe and bioavailable, so that they can be absorbed through the gastrointestinal tract in high enough concentrations to have the same effect on cancer as curcumin does when it is observed in the laboratory.
What do you think will be the main hurdles that need to be overcome?
The main hurdle from my standpoint is figuring out a way to find an appropriate compound that can be given safely to patients to increase intracellular PIAS3, while not having a negative effect on other cells. This may be something that can be achieved with curcumin and its analogues or it may come from other sources and that's what we're trying to find out.
Where can readers find more information?
The Mesothelioma Foundation in the United States provides a lot of information about mesothelioma, as well as the National Cancer Institute.
In terms of this particular piece of research, I think we will need to wait a few years until we have obtained additional findings before we can get the information out there.
About Dr. Afshin Dowlati
Dr. Afshin Dowlati is a Professor of Medicine in the Division of Hematology and Oncology at Case Western Reserve University where he holds the Rosalie and Morton Chair in Lung Cancer. He has also been awarded Lucile and Robert H. Gries Endowed Director, Center for Cancer Drug Development. He is Co-Leader of the Developmental Therapeutic Program at Case Comprehensive Cancer Center and leads both the Phase I and Thoracic Programs at University Hospitals Seidman Cancer Center.
His current laboratory research focuses on signal transduction in lung and target discovery in Small Cell Lung Cancer. His Phase I Program is nationally and internationally recognized with focus on scientific drug development, first in human studies and novel early phase trial design.
Dr. Dowlati graduated from the University of Liege Medical School in Belgium 1992, and subsequently trained both in Belgium and Cleveland in Hematology and Oncology. Dr. Dowlati has published over 120 peer reviewed articles focusing on his own original research.
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