A new study presented at the American Association for Cancer Research (AACR) Targets and Cancer Therapeutics Conference has reported that the anti-diabetes drug metformin increases the effectiveness of radiotherapy by reducing the fraction of cancer stem cells in cancer cell populations. Cancer stem cells are resistant to treatment with radiation and chemotherapy. However, complete control or cure of cancer is not possible without eradicating the stem cell population. The study was designed to investigate the effect of metformin on cancer stem cells, including cells subjected to mild heat or radiation.
The Akt/mTOR signaling pathway has been shown to play a critical role for survival and proliferation of cancer cells, particularly cancer stem cells. To conduct the study, the authors tested the impact of (1) metformin, (2) ionizing radiation, and (3) mild heating, alone or in combination, on mTOR activity and survival of cancer stem cells. Metformin was shown to inactivate mTOR via activation of AMPK, which resulted in the preferential killing stem cells of various cancer cell types. For example, 3.4% of a population of MCF-7 breast cancer cells were cancer stem cells before treatment with metformin for 48 hours; it decreased to 1.2% as a result of treatment. Metformin also was found to selectively kill the stem cells of a population of MIAPaCa-2 pancreatic cancer cells. Irradiation and mild heating also suppressed mTOR activity through activation of AMPK. However, irradiation did not result in the death of cancer stem cells, while heating was effective in killing them. Significantly, irradiation was found to upregulate Akt activity whereas mild heating downregulated Akt activity. It appears that the radiation-induced inhibition of mTOR activity was counterbalanced by Akt activation. Treatment of MIAPaCa-2 cancer xenografts with a combination of metformin plus irradiation in an animal model of pancreatic cancer was found to be markedly more effective than metformin or irradiation alone. The authors conclude that metformin in combination with ionizing radiation or mild hyperthermia is potentially effective in eradicating cancer stem cells.
Comments regarding the study
Metformin, which is used to treat type 2 diabetes, is thought to influence cancer cells either through insulin-mediated effects or by directly affecting cell proliferation and apoptosis (programmed cell death). This is the first study that has reported that metformin might enhance the effectiveness of radiation treatment by killing breast cancer stem cells.
Breast cancer is considered incurable since it can metastasize decades after treatment. Most such late recurrences are hormone receptor positive. It has not been determined how this occurs. Under one theory, breast cancer cells can exist in a quiescent state, thereby avoiding being eliminated by radiation treatment or chemotherapy that might be effective against the same cells when they are actively dividing. Some researchers have suggested that such dormant cells might actually be breast cancer stem cells, which lack the cell receptors of breast cells and, as such, are also insensitive to endocrine treatment. Based on the study results, breast cancer patients can be reassured that metformin will not interfere with radiation treatment and may, in fact, improve its effectiveness.