Selective acidification and de-energization of WM983B melanoma xenografts and sensitization to doxorubicin following lonidamine administration

Synopsis: WM983B melanoma xenografts exhibit a significant selective decrease in their intracellular pH following treatment with 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. Energetics is further attenuated by inhibition of electron transport, but the site of inhibition is not as well understood. 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 WM983B melanomas with doxorubicin following tumor acidification with LND demonstrates the potential clinical utility of combining LND with doxorubicin in the treatment of melanoma and other human cancers.

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