Abstract #0529
Selective acidification and de-energization of WM983B melanoma xenografts and sensitization to doxorubicin following lonidamine administration
Kavindra Nath 1 , David S Nelson 1 , Daniel F Heitjan 1 , Rong Zhou 1 , Dennis B Leeper 2 , and Jerry D Glickson 1
1
University of Pennsylvania, Philadelphia,
Pennsylvania, United States,
2
Thomas
Jefferson University, Pennsylvania, United States
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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