MESOTHELIOMA CURCUMIN SLOWS DISEASE PROGRESSION
A common Asian spice
and cancer-hampering molecules show promise in slowing the progression of
mesothelioma, a cancer of the lung's lining often linked to asbestos.
Scientists from Case Western Reserve University and the Georg-Speyer-Haus in
Frankfurt, Germany, demonstrate that application of curcumin, a derivative of
the spice turmeric, and cancer-inhibiting peptides increase levels of a protein
inhibitor known to combat the progression of this cancer. Their findings
appeared in the Aug. 14 online edition Clinical
Cancer Research; the print version of the article will appear
Oct. 1.
Malignant mesothelioma
has received widespread notoriety because it occurs frequently in the lung
linings of people exposed to asbestos. However, asbestos does not always cause
this particular cancer that kills 43,000 people worldwide each year. Many
mesothelioma patients were never exposed to asbestos.
"Mesothelioma is
a disease that continues to have a significant burden worldwide, and the
treatment option is really suboptimal. We must find better ways to treat
it," said senior author Afshin Dowlati, MD, Professor of Medicine --
Hematology/Oncology, Case Western Reserve University School of Medicine, and
member of the Case Comprehensive Cancer Center. "We now understand the
mechanisms that drive cell proliferation and growth in malignant
mesothelioma."
The culprit in
sparking many cancers, particularly mesothelioma, is the intracellular protein
and transcription factor STAT3 (signal transducer and activator of
transcription 3). A signal transducer and activator is a pathway for
instructing the growth and survival of cells, and a transcription factor is a
protein that controls genetic information directing cells how to perform. STAT3
is notorious for sending signals to trigger the onset of human cancers and to
fuel their continued growth. The great neutralizer of STAT3 is PIAS3 (protein
inhibitor of activated STAT3). PIAS3 possesses the strength to inhibit and
block STAT3's ability to cause cancer.
In this study,
investigators assessed PIAS3 expression in tissue samples of mesothelioma solid
tumors and the protein inhibitor's subsequent effects on STAT3 activity. Tissue
samples came from three different locations in the country, and information
logged for each specimen detailed how long the patient lived and the types of
mesothelioma they had. Investigators then linked the levels of PIAS3 with STAT3
activity in each sample. Additionally, investigators examined the effects of
curcumin and peptides extracted from PIAS3 segments on malignant mesothelioma
cells in vitro.
"In those
mesothelioma patients where PIAS3 is low, indeed STAT3 is activated," said
Dowlati, Director of the Center for Cancer Drug Development at University
Hospitals Seidman Cancer Center. "Mesothelioma patients who have low PIAS3
and high STAT3 have a greater chance of dying early. On the flip side, those
patients with a high PIAS3 levels have a 44 percent decreased chance of dying
in one year, which is substantial."
Investigators also
found that curcumin and PIAS3 peptides raised PIAS3 levels, which brought down
STAT3 activity and caused mesothelioma cells to die. Their study served as
proof of principle about the effectiveness of these two compounds in treating
malignant mesothelioma, a first step in moving a treatment toward clinical
trials. Additionally, their findings demonstrated that PIAS3 could serve as a
predictive marker for managing mesothelioma because the disease's tumors do not
always progress in a consistent, predictable manner, even when tumor stages,
grades and clinical presentations appear similar.
"Our findings
suggest that PIAS3 expression positively affects survival in mesothelioma
patients and that PIAS3 activation could become a therapeutic strategy,"
Dowlati said. "Our interest for the future is that we want to find better,
more simple ways to increase intracellular levels of PIAS3 for malignant
mesothelioma through the use of synthetic PIAS3 peptide or curcumin analogs. We
must develop a curcumin analog that is absorbable by the human body. Currently,
curcumin ingested as the spice turmeric has practically no absorption within
the gut."
Their investigation
also contributes to the overall body of scientific knowledge for all cancer.
"Our findings beg
the question of what role PIAS3 could play in limiting STAT3 activation in other
cancers as well," Dowlati said. "There is an opportunity to extend
this discovery because a number of cancers are STAT3-activated."
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