Regular use of aspirin has been known to protect against heart disease. A new study has shown benefits that extend beyond the heart, also helping reduce colorectal tumor growth and prevent relapse of the cancer. The study titled, “A comprehensive in vivo and mathematic modeling-based kinetic characterization for aspirin-induced chemoprevention in colorectal cancer,” was published on the 6th of January 2020 in the latest issue of the journal Carcinogenesis.
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Finding the correct dose.
According to the lead researcher of the study Dr. Ajay Goel, and chair of the Department of Molecular Diagnostics, Therapeutics and Translational Oncology at the City of Hope, the problem lies in determining the dose of aspirin that can be prescribed regularly, giving protection from the cancer, whilst not causing side effects.
Some might say aspirin is a 'miracle drug' because of its potential to prevent diseases that result from chronic inflammation, such as cancer, Alzheimer's, Parkinson's and arthritis. The reason aspirin isn't currently being used to prevent these diseases is because taking too much of any anti-inflammatory eats at the stomach's mucus lining and causes gastrointestinal and other problems. We are getting closer to discovering the right amount of daily aspirin needed to treat and prevent colorectal cancer without causing scary side effects.”
Dr. Ajay Goel
For the study, researchers used mice models, translating their findings to humans using mathematical modeling and analysis. Using these complex analyses, they tried to assess the daily quantity of aspirin consumed by people of the United States and Europe. Their results on mice revealed that as the dose of aspirin rose, the rate of cell death rose on one hand, alongside the division rates of the cells reducing.
The reduction in the division of the cells was one of the reasons that aspirin could help in halting the growth of tumor cells. Furthermore, the increased rate of cell death would also mean the death of the tumor cells, preventing their proliferation.
Goel said in a statement, “We are now working with some of the people conducting those human clinical trials to analyze data and use mathematical modeling. This process adds a layer of confidence to the findings and guides future human trial designs.”
Therefore, the dose of aspirin that could protect against colorectal cancer recurrence would also be more evident, he said. He pointed out the colorectal cancer is one of the top five cancers diagnosed annually.
For the study, three different doses of aspirin on four colorectal cancer cell lines in the lab were studied. These cell lines included tumors containing mutations in the PIK3CA gene and those with microsatellite instability. These pathological changes in the tumor cell lines have been known to raise the risk of colon cancers, endometrial or uterine cancers alongside aggressive forms of breast cancers.
The four different doses of aspirin were; control, low-dose aspirin (15mg/kg), medium-dose aspirin (50mg/kg) and high-dose aspirin (100mg/kg). For mice, these were equivalent of 100mg, 300mg, and 600mg for humans.
The 432 mice with tumors were treated with the drugs, after dividing them into four groups. At various points in the study, (three, five, seven, nine and eleven days) three mice were chosen from each group and their tumors analyzed.
Results showed that with increasing doses of aspirin, there was an increase in programmed cell death or apoptosis. The percentage of cells that died due to apoptosis rose in all the cell lines that were studied.
The team concluded that raising the dose of aspirin, triggered a domino-like effect leading to cell death of the colorectal cancer cell lines. This apoptosis was seen in all the cell lines irrespective of their genetic makeup.
The team wrote, “We observed that aspirin resulted in a dose-dependent decrease in the cell division rate, and a concomitant increase in the cell death rates in xenografts from all cell lines. Aspirin significantly inhibited cell proliferation as measured by Ki67 staining (P < 0.05–0.01). The negative effect of aspirin on the rate of tumor cell proliferation was more significant in xenograft tumors derived from PIK3CA mutant versus wild-type cells.”
As a next step, a mathematical model was applied to the experimentally obtained data. The rates of cell division and cell death were also analyzed to see if tumor cells could survive and develop into tumors.
They wrote, “A computational model of 3D-tumor growth suggests that the growth inhibitory effect of aspirin on the tumor growth kinetics is due to a reduction of tumor colony formation and that this effect is sufficiently strong to be an important contributor to the reduction of CRC incidence in aspirin-treated patients.”
The authors of the study concluded:
In conclusion, we provide detailed kinetics of aspirin-mediated inhibition of tumor cell proliferation, which supports the epidemiological data for the observed protective effect of aspirin in CRC patients.”
This study was funded by the National Institutes of Health's National Cancer Institute, Cancer Prevention Research Institute of Texas, Baylor Foundation and Baylor Scott & White Research Institute.
Shimura, T., et al. (2020). A comprehensive in vivo and mathematic modeling-based kinetic characterization for aspirin-induced chemoprevention in colorectal cancer. Carcinogenesis. https://doi.org/10.1093/carcin/bgz195