Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Simple Summary Dysregulated metabolism is a key hallmark of cancer cells and many solid tumors are acidic. Acidosis is responsible for cancer aggressiveness and for resistance to several treatments. In the present study, we evaluated to which extent tumor acidosis was influenced upon inhibition of the import of pyruvate into the mitochondria, the powerhouse of the cell. Using advanced molecular imaging to measure non-invasively the acidity in a model of breast cancer, we found that while some tumor regions became much more acidic, others did not show any change. This study highlights the capacity of this advanced technology to reveal the heterogeneity of response to the treatment. (1) Background: The acidosis of the tumor micro-environment may have profound impact on cancer progression and on the efficacy of treatments. In the present study, we evaluated the impact of a treatment with UK-5099, a mitochondrial pyruvate carrier (MPC) inhibitor on tumor extracellular pH (pHe); (2) Methods: glucose consumption, lactate secretion and extracellular acidification rate (ECAR) were measured in vitro after exposure of cervix cancer SiHa cells and breast cancer 4T1 cells to UK-5099 (10 mu M). Mice bearing the 4T1 tumor model were treated daily during four days with UK-5099 (3 mg/kg). The pHe was evaluated in vivo using either chemical exchange saturation transfer (CEST)-MRI with iopamidol as pHe reporter probe or P-31-NMR spectroscopy with 3-aminopropylphosphonate (3-APP). MR protocols were applied before and after 4 days of treatment; (3) Results: glucose consumption, lactate release and ECAR were increased in both cell lines after UK-5099 exposure. CEST-MRI showed a significant decrease in tumor pHe of 0.22 units in UK-5099-treated mice while there was no change over time for mice treated with the vehicle. Parametric images showed a large heterogeneity in response with 16% of voxels shifting to pHe values under 7.0. In contrast, P-31-NMR spectroscopy was unable to detect any significant variation in pHe; (4) Conclusions: MPC inhibition led to a moderate acidification of the extracellular medium in vivo. CEST-MRI provided high resolution parametric images (0.44 mu L/voxel) of pHe highlighting the heterogeneity of response within the tumor when exposed to UK-5099.

Automated summary

The dysregulated metabolism and acidosis in tumors play a crucial role in cancer progression and drug resistance. Inhibiting mitochondrial pyruvate carrier (MPC) can lead to tumor acidification, but the response to this treatment varies within the tumor, as shown by high-resolution CEST-MRI parametric images.