1Radiology, University of Pennsylvania, Philadelphia, PA, United States; 2Pharmacology, University of Pennsylvania, Philadelphia, PA, United States; 3Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, United States
Synopsis: The inverted pH gradient between the inside and outside of cells that is observed in tumors presents both obstacles to and opportunities for cancer therapy. As a consequence of their high levels of aerobic glycolysis, DB-1 melanoma xenografts exhibit a selective decrease in their intracellular pH by ~0.6 units following treatment with the lonidamine (LND), which inhibits the export of lactic acid from the tumor cell via the monocarboxylic acid transporter (MCT). In addition, LND decreases the bioenergetics state of the tumor by inhibiting transport of pyruvate into mitochondria via the mitochondrial pyruvate carrier (MPC). Under these conditions, doxorubicin accumulates in the tumor as a result of protonation of its amino group (i.e., cation trapping), which produces a pronounced enhancement of the antineoplastic activity of this anthracycline. Treatment of DB1 melanomas with doxorubicin following tumor acidification with LND produced long-term (>50 day) growth delays in four out of five melanoma xenografts demonstrating the potential clinical utility of combining LND with doxorubicin in the treatment of melanoma and other human cancers.