“We were interested in finding an agent that could combat the pain and numbness associated with chemotherapy yet not interfere with the anti-tumor effects of treatment,” said Heijnen. “Metformin is inexpensive and widely used, and it has few side effects. As an added bonus, in vitro and in vivo studies suggest that metformin has anti-tumor effects of its own.”
Using test mice and control mice to determine their findings, investigators treated mice with saline, the chemo drugs cisplatin or paclitaxel and either metformin or saline. The metformin was administered at the same time or before cancer treatment began, 30-60 minutes before the cisplatin.
During the study, both pain and numbness were examined. To measure pain sensitivity, the hind paw of the mouse was stimulated with fibers of increasing force. It is already known that chemotherapy increases the sensitivity to pain, and mice treated with chemotheraputics withdraw their paw at a lower force than control mice. Metformin prevented increased pain sensitivity.
To test numbness, the team used a newly developed assay in which an adhesive patch was placed on the hind paw of each test or control mouse. Typically, mice will attempt to remove the patch as soon as they feel it.
“In cisplatin-treated control mice, this response time was significantly prolonged, suggesting that peripheral neuropathy was preventing them from sensing the patch. The metformin-treated mice responded to the patch within a normal timeframe,” said Heijnen. “When we examined the epidermal tissue of both test and control mice, we saw clear retraction of intra-epidermal nerve fibers in the cisplatin-treated control mice — an expected result of chemotherapy — but no retraction in the metformin-treated mice.”
Heijnen and her research team also are studying the effect of metformin in preventing neuronal damage in the brain known as chemobrain.
“Metformin is proven to be safe and well tolerated. Our goal is for physicians to become advocates of administering it before treatment to offset chemotherapy-induced neuropathy, “she said.
Heijnen’s group plans to test the drug with other chemotherapy agents and with chemoradiation therapy.
There also is hope that the drug’s anti-tumor effects may reduce cancer risk among diabetics.
The PLOS One article cited a retrospective study of breast cancer patients with diabetes that demonstrated metformin inhibited cancer cell growth. According to investigators, “those treated with metformin had higher complete pathologic response rates to neoadjuvant therapy than did the patients treated with other anti-diabetic drugs.”
Heijnen said the results emphasize the need to collect clinical data, including patient report of symptoms and side effects during cancer treatment. If two treatment options resulted in similar clinical outcomes, being able to choose the one that produced fewer side effects could greatly benefit patients.
“Symptoms are finally getting the attention, and physicians and researchers are taking pain and neuropathy into account. These side effects can be dose-limiting during treatment and persist for many months or even years, well into survivorship,” said Heijnen. “It’s important for patients to report their side effects so that we can preserve their quality of life, as well as improve their outcomes.”