Colorectal cancer: How Metformin could help slow cancer cell growth

The researchers treated HCT116 colorectal cancer cells — a highly aggressive type of cancer cell line — with a sub-lethal dose (2.5mM) of metformin.

Using several different techniques to analyze the drug’s effects on the cells’ RNA, they found that metformin altered the activity of some microRNAs (miRNAs, which are short, single-stranded lengths of RNA that regulate genes). Some were upregulated, meaning their activity increased; others were downregulated.

“In this particular study, there is some suggestion that metformin may play a role in the downregulation of genes specific to colon cancer,” Nilesh Vora, MD, board certified hematologist and medical oncologist and medical director of the MemorialCare Todd Cancer Institute at Long Beach Medical Center in Long Beach, CA, told Medical News Today.

It’s a novel mechanism that may have implications in other cancers. Since metformin is a relatively harmless and low-cost drug, this may have a tremendous impact on other cancers,” Vora noted.

Metformin is a widely available therapy for type 2 diabetes, the prevalence of which is expected to rise to 700 million by 2045. The medication helps the body respond to insulin — the hormone that controls blood glucose. It also decreases the amount of sugar that the liver produces and that the intestines or stomach absorb. However, studies have not yet uncovered the precise mechanisms underlying these effects.

, surgical oncologist, and the chief of medicine and director of the Gastrointestinal and Hepatobiliary Program at Providence Saint John’s Cancer Institute in Santa Monica, CA, explained to MNT:

“Metformin is typically used to treat type 2 diabetes and although it has been shown to have an anti-cancer effect the mechanism has not been well understood. This study provides a possible mechanism through micro RNAs inhibiting cell growth and proliferation. This is particularly important since it opens the potential to develop novel therapeutic strategies targeting these micro RNAs.”

Two upregulated miRNAs — miR-2110 and miR-132-3p — directly targeted a gene signaling pathway often disrupted in human cancers. This slowed down the rate at which the cancer cells grew and multiplied.

Another two miRNAs — miR-222-3p and miR-589-3p — targeted another pathway, which resulted in suppressed cell growth and delaying of the cell cycle.

If similar effects are seen in tumors in people and not just cells, these findings with metformin could potentially lead to alternative treatments for some cancers.

“Metformin has been available for a long time and is relatively inexpensive,” Bilchik said. “There is potential for its use to be extended to other cancers, but more important, this study provides insights into the development of novel therapeutic agents.”

The researchers caution that their findings were in isolated cells that were cultured in a high-glucose medium, which does not exactly mimic the conditions found in the human body.

However, they recommend that their experiments be repeated using cells cultured in media that more closely resemble the physiological nutrient levels found in tumors.

RNA therapeutics are a new approach to cancer treatment. Research shows that noncoding RNAs (which include the microRNAs in this study) are dysregulated in many types of cancer, including:

Some miRNAs increase the likelihood of cancers, others decrease it, and the same miRNA can have different effects on different cancers.

MiRNAs have two advantages over other cancer treatments — they are naturally occurring molecules in cells and they target several genes in one pathway. This means that they can cause a broad, but specific response. Currently, several studies are investigating the use of miRNAs as cancer therapeutics, particularly how they can be delivered into cells.

This study provides new insights into metformin’s effect on the molecular mechanisms inside cells and why it reduces proliferation of cancer cells, emphasising the role of miRNAs in colorectal cancer.

The authors suggest their findings highlight the potential for developing RNA therapeutics for cancer prevention and treatment and possibly for targeted interventions. Although there are several challenges in the field of miRNA therapeutics, this study could signal another step in their development as potential cancer treatments.