Research led by the University of Saskatchewan in Canada has discovered that the diabetes drug metformin might reduce the development of multidrug resistance in vitro in breast cancer cells and may reverse resistance once it has occurred.

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MDR could be delayed, prevented, or reversed using metformin.

Terra Arnason, Ph.D. — an associate professor and clinician scientist in the Department and College of Medicine — and colleagues led the study. Their findings were published in the journal PLOS ONE.

Multidrug resistance (MDR) occurs when several cancers develop resistance to chemotherapy drugs. MDR is a significant factor in the failure of many types of chemotherapy, and it is often a terminal event. It affects individuals with blood cancers and solid tumors, including those with breast cancer.

How and why cancer cells become resistant to drugs has remained an important question in cancer research. The answer would provide potential targets to prevent and reverse resistance to treatment.

People who develop resistance to one agent frequently develop resistance to many, hence being known as “multiple drug resistance.”

Arnason and team aimed to investigate the effect of metformin on MDR when used together with the primary treatment.

Metformin is a drug used to treat type 2 diabetes when diet and exercise alone have not helped to control blood sugar levels. Metformin helps to lower blood sugar by improving the way the body manages insulin.

In previous research, metformin has been shown to have an antiproliferative effect on tumor cells, meaning that the drug inhibits the growth and spread of cancer cells.

In fact, people with type 2 diabetes and cancer who take metformin have been reported to have a 31 percent reduction in the occurrence of new cancers. Also, metformin has been suggested to benefit all-cause survival in those with breast cancer.

The team planned to evaluate the mechanisms that facilitate metformin’s antiproliferative impact and test whether using metformin pretreatment could benefit or interfere with MDR cancer.

They used the widely studied MCF7 breast cancer cell lines and tested them for resistance to the chemotherapy drug doxorubicin in order to assess the antiproliferative effect of metformin.

Arnason and colleagues found that metformin had an antiproliferative effect on MCF7, including the cells that were resistant to doxorubicin.

The development of drug resistance was delayed or prevented in cells that were pretreated with metformin. And, experiments conducted in cells cultures and mouse models of aggressive breast cancer uncovered that MDR was reversed after its onset by metformin use.

Together, the findings demonstrate the potential for metformin to be utilized as a therapy to prevent or reverse MDR. The authors write:

We have demonstrated that metformin monotherapy has an antiproliferative effect on multiple cell lines, including those selected for resistance to doxorubicin, in a dose-dependent manner.”

“The effect is also observed,” the study authors conclude, “when metformin is used in combination with other anticancer treatments in breast cancer cells.”

“Our findings are consistent with the growing literature base demonstrating metformin’s ability to slow the growth of tumor cells in vitro.”

Future work by the team will involve analyzing cancer cells over many months to observe whether the effect of metformin is short- or long-term.