J Nucl Med. 2013 Feb;54(2):252-8.
Purpose: Over the last several years, epidemiologic data have suggested that the antidiabetes drug metformin (MET), an adenosine monophosphate–activated protein kinase (AMPK) activator, improves progression-free survival of patients with multiple cancers; more than 30 clinical trials are under way to confirm this finding. We postulated that the role of AMPK as a central cellular energy sensor would result in opposite effects on glucose uptake and proliferation, suggesting different roles for 18F-FDG and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) in assessing its effectiveness as an antineoplastic agent.
Methods: Colon cancer cell lines HT29 (human) and MC26 (murine) were treated for 24 or 72 h with a range of MET concentrations (0–10 mM). Western blotting was used to study the activation of AMPK after MET treatment. Glucose uptake and cell proliferation were measured by cell retention studies with either 18F-FDG or 18F-FLT. EdU (ethynyl deoxyuridine, a thymidine analog) and annexin-propidium iodide flow cytometry was performed to determine cell cycle S-phase and apoptotic changes. In vivo 18F-FDG and 18F-FLT PET images were acquired before and 24 h after MET treatment of HT29 tumor–bearing mice.
Results: After 24 h of MET incubation, phosphorylated AMPK levels increased severalfold in both cell lines, whereas total AMPK levels remained unchanged. In cell retention studies, 18F-FDG uptake increased but 18F-FLT retention decreased significantly in both cell lines. The numbers of HT29 and MC26 cells in the S phase decreased 36% and 33%, respectively, after MET therapy. Apoptosis increased 10.5-fold and 5.8-fold in HT29 and MC26 cells, respectively, after 72 h of incubation with MET. PET imaging revealed increased 18F-FDG uptake (mean ± SEM standardized uptake values were 0.71 ± 0.03 before and 1.29 ± 0.11 after MET therapy) (P < 0.05) and decreased 18F-FLT uptake (mean ± SEM standardized uptake values were 1.18 ± 0.05 before and 0.89 ± 0.01 after MET therapy) (P < 0.05) in HT29 tumor–bearing mice.
Conclusion: MET, through activation of the AMPK pathway, produces a dose-dependent increase in tumor glucose uptake while decreasing cell proliferation in human and murine colon cancer cells. Thus, changes in 18F-FDG uptake after MET treatment may be misleading. 18F-FLT imaging is a promising alternative that correlates with the tumor response.