title: Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin.
abstract: We demonstrate that the effects of lonidamine (LND, 100 mg/kg, i.p.) are similar for a number of xenograft models of human cancer including DB-1 melanoma and HCC1806 breast, BT-474 breast, LNCaP prostate and A2870 ovarian carcinomas. Following treatment with LND, each of these tumors exhibits a rapid decrease in intracellular pH, a small decrease in extracellular pH, a concomitant monotonic decrease in nucleoside triphosphate and an increase in inorganic phosphate over a 2-3 h period. We have previously demonstrated that selective intracellular tumor acidification potentiates response of this melanoma model to melphalan (7.5 mg/kg, i.v.), producing an estimated 89% cell kill based on tumor growth delay analysis. We now show that, in both DB-1 melanoma and HCC1806 breast carcinoma, LND potentiates response to doxorubicin, producing 95% cell kill in DB-1 melanoma at 7.5 mg/kg, i.v. doxorubicin and 98% cell kill at 10.0 mg/kg doxorubicin, and producing a 95% cell kill in HCC1806 breast carcinoma at 12.0 mg/kg doxorubicin. Potentiation of doxorubicin may result from cation trapping of the weakly basic anthracycline. Recent experience with the clinical treatment of melanoma and other forms of human cancer suggests that these diseases will probably not be cured by a single therapeutic procedure other than surgery. A multimodality therapeutic approach will be required. As a potent modulator of tumor response to N-mustards and anthracyclines as well as tumor thermo- and radiosensitivity, LND promises to play an important clinical role in the management and possible complete local control of a number of prevalent forms of human cancer.
authors.affiliation: Laboratory of Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kavindra
authors.initials: K
authors.lastname: Nath
authors.forename: David S
authors.initials: DS
authors.lastname: Nelson
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.forename: Dennis B
authors.initials: DB
authors.lastname: Leeper
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Glickson
mesh_terms: D000143:Acids / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000172:deficiency*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000494:pharmacology*; D042541:Intracellular Space / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D027981:Symporters / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000143:Acids; D000255:Adenosine Triphosphate; D004317:Doxorubicin; D007191:Indazoles; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C016371:lonidamine
keywords: doxorubicin; lonidamine; monocarboxylate acid transport inhibitor; tumor acidification; tumor de-energization