Some recent treatments for diabetes may enhance the spread of cancer, suggest the results of a study conducted in mice.
Researchers found that the dipeptidyl peptidase (DPP)–4 inhibitors saxagliptin and sitagliptin, as well as the antioxidant alpha-lipoic acid, increased the risk of existing tumours metastasising.
While the drugs do not increase the initial risk of developing cancer, the finding has led the researchers to call for caution when using the drugs to treat patients with existing cancer.
“The results we present here indicate that saxagliptin and sitagliptin enhance cancer cells’ mobility and invasive capacity and may promote tumour metastasis,” say the researchers, led by Hongting Zheng from the department of endocrinology at Xinqiao Hospital in Chongqing, China.
Diabetes is increasing among the general population — the World Health Organization estimates that the number of adults living with the disease globally has quadrupled since 1980 to 422 million adults — and the disease is associated with an increased risk of cancer. Research has examined the effect of diabetes drugs on the risk of developing cancer but the effect these treatments has on cancer once it is established has not been assessed. Previous research has found that antioxidants can increase the spread of cancer by making cancerous cells more resistant to oxidative stress, which would ordinarily cause damage to the cells and hinder their survival.
Zheng’s team performed a meta-analysis to assess the effect of DPP-4 inhibitors on the incidence of cancer and found no increase. However, using in vitro cell cultures of cancers commonly associated with diabetes, they found that saxagliptin and sitagliptin markedly increased migration and invasion of the cells. In a tumour-bearing mouse model, the drugs significantly increased the number of metastatic nodules in the liver and lungs.
The researchers showed that the drugs’ effects were likely to be mediated through activation of the nuclear factor E2–related factor 2 (Nrf2) pathway. Nrf2 is one of the cell signalling pathways that responds to antioxidants by helping to protect cells – its activation was also correlated with tumour spread.
The antioxidant alpha-lipoic acid is used by some people with diabetes to relieve neuropathic pain, so the researchers tested its ability to enhance metastasis. Similarly to saxagliptin and sitagliptin, alpha-lipoic acid activated Nrf2 and increased the burden of metastatic nodules in the mouse model.
The researchers, reporting the results in Science Translational Medicine
(online, 13 April 2016), conclude: “Our findings suggest that antioxidants that activate NRF2 signalling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumour metastasis.”
 Wang H, Liu X, Long M et al. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Science Translational Medicine 2016. doi: 10.1126/scitranslmed.aad6095