Multimodality imaging assessments of response to metformin therapy for breast cancer in nude mice

Abstract

Background Metformin is the most widely used anti-diabetic drug in the world. An increasing body of evidence shows metformin also blocks cell cycle progression and selectively induces apoptosis via caspase activation in some breast tumor cells. Diffusion-weighted imaging (DWI) and bioluminescence imaging (BLI) have great potential in the evaluation of the early response to cancer therapies. We used DWI and BLI in evaluating the response of breast cancer to metformin. Methods The luciferase-engineered human breast cancer cell line MDA-MB-231 was inoculated into the mammary fat pad of nude mice. Twelve female nude mice bearing tumors were divided into two groups. The mice in the treatment group received metformin (2 mg/ml in drinking water daily) after tumor inoculation, and the mice in the control group were offered drinking water without any drug added. We performed 7T magnetic resonance imaging and optical imaging every week. Imaging included T1- and T2-weighted imaging, DWI, and BLI. After imaging. The tumors were collected and subjected to histological analysis. Results The mean photons/second of tumors in the treatment group was (3.00±0.43)×106 at day one, (1.01±0.14)×107 at 2 weeks, (5.79±1.42)×107 at 4 weeks, and (2.33±0.70)×107 at 8 weeks. The mean photons/second of tumors in the control group was (3.29±0.59)×106 at day one, (3.59±0.63)×107 at 2 weeks, (3.87±0.56)×108 at 4 weeks, and (4.12±1.72)×108 at 8 weeks. Compared to the control group, the treatment group showed an obvious decrease in the mean bioluminescence (photons/s) of the tumors and fewer metastases. Histological examination confirmed the presence of fewer metastases. DWI showed the apparent diffusion coefficient (ADC) value of the tumors; the mean ADC value was (0.9287±0.04346)×10-3 mm2/s in the treated tumors and (0.7553±0.01804)×10-3 mm2/s in the untreated tumors. The ADC value of tumors in the treatment group was significantly higher than the control tumors (P=0.0013). Conclusions The growth and metastasis of MDA-MB-231 breast cancer may be inhibited by metformin. DWI and BLI have great potentials in the evaluation of the early response to metformin treatment. BLI has a high degree of sensitivity and is able to detect micrometastasis, thus can be used for identifying tumor metastasis in vivo.