Three SGLT2 inhibitors are FDA approved for the treatment of hyperglycemia in type 2 diabetes, but could these drugs have a role in the treatment of other diseases?
Possibly, says a new study that looked at the effects of SGLT2 inhibitors in pancreatic and prostate cancer. Results from the study suggested that SGLT2 inhibitors could play a role in decreasing the growth and viability of these types of tumors. The study, by Claudio Scafoglio, MD, PhD and colleagues at the David Geffen School of Medicine at the University of California Los Angeles and University of Wurzberg in Germany, was recently published online.
The findings rest on the premise that cancer cells need high glucose levels to maintain growth and survival. Past studies have suggested that passive glucose transporters (GLUT) may help cancer cells get the large amounts of glucose they need. But there may be more going on than that. Radioactively labeled GLUT1 probes have been unreliable for detecting these cancers and are not recommended for diagnosis and staging. GLUTs are also found widely in heart, muscle, brain, and other organs, so they’re not ideal as targets for cancer therapy.
The present study suggests a new mechanism for how pancreatic and prostate cancer cells obtain glucose: active transport via SGLT receptors. If that’s true, radioactively labelled probes specific for SGLTs could be used along with PET imaging to diagnose and stage pancreatic and prostate cancers.
In the study, the researchers performed three main experiments. First, they did immunohistochemical staining to map SGLT1 and SGLT2 receptors in human pancreatic and prostate tumors. Second, they measured glucose uptake in tumors freshly isolated from patients. To do this, they used a radioactively labeled probe (called Me4FDG) that was selective for SGLT, and not transported by GLUTs. Finally, they looked at the effects of SGLT2 inhibitors on tumor growth in mouse models of pancreatic and prostate cancer.
Key Results included:
• Pancreatic and prostate cancers express SGLT1 and SGLT2.
♦ The SGLT1 labeled antibody reacted mostly with nuclei, and the SGLT2 labeled antibody reacted mainly with the cytoplasm in samples from 9/9 pancreatic and 8/9 prostatic cancer patients.
• SGLTs expressed in pancreatic and prostate tumors function in glucose uptake:
♦ Phlorizin (a nonselective SGLT inhibitor) and dapagliflozin (a selective SGLT2 inhibitor) blocked Me4FDG uptake in three samples of pancreatic adenocarcinoma and three samples of prostate adenocarcinoma.
♦ Me4FDG accumulation correlated with areas where cancer cells expressed SGLT2.
• In mouse models of pancreatic and prostate cancer, treatment with dapagliflozin blocked the uptake of Me4FDG by 40-50%.
• Pancreatic tumors grafted into mice treated with canagliflozin, dapagliflozin, or the cancer drug gemcitabine for four weeks showed:
♦ There were similar decreases in growth rates in 6 mice treated with gemcitabine compared to 6 mice treated with canagliflozin, with weekly tumor growth rates for both drugs lower than placebo (38% vs 43% vs 63%, respectively).
♦ Canagliflozin reduced tumor growth and increased cell death in the tumor center, whereas gemcitabine reduced tumor growth but not cell death.
♦ Dapagliflozin caused significant increases in tumor cell death compared to placebo in 15 mice (35% vs 21%, respectively, P=0.001), though decreases in tumor growth were nonsignificant.
♦ SGLT inhibitors decreased viability of cancer cells, and might potentiate the action of anticancer drugs like gemcitabine.
“[O]ur demonstration of the functional expression of SGLT2 in pancreatic and prostate carcinomas opens new diagnostic and therapeutic possibilities for these common cancers. We suggest that Me4FDG-PET may be useful in the diagnosis and staging of these cancers; in addition, SGLT2 drugs developed to treat diabetes may be useful in treating these cancers, either alone or in combination with other antitumor drugs,” the authors concluded, “… [I]n the case of tumors expressing SGLT2, such as pancreatic and prostate cancers, we predict that the diabetes drugs will reduce glucose uptake, disrupt glycolysis, and reduce tumor growth without significant side effects.”
Reference: Scafoglio C, et al. Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci. Published online 13 July 2015.