Inhibitory Effect of the Noncamptothecin Topoisomerase I Inhibitor LMP-400 on Female Mice Models and Human Pheochromocytoma Cells.
Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Jan
J
Schovanek
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Petra
P
Bullova
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Yasin
Y
Tayem
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Alessio
A
Giubellino
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Robert
R
Wesley
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Nikoletta
N
Lendvai
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Svenja
S
Nölting
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Juraj
J
Kopacek
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Zdenek
Z
Frysak
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Yves
Y
Pommier
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Shivaani
S
Kummar
Program in Reproductive and Adult Endocrinology (J.S., P.B., Y.T., A.G., N.L., S.N., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Warren G. Magnuson Clinical Center (R.W.), and National Cancer Institute (Y.P., S.K.), National Institutes of Health, Bethesda, Maryland 20892-1109; Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology (J.S., Z.F.), Faculty of Medicine and Dentistry, Palacky University, 771 47 Olomouc, Czech Republic; Department of Molecular Medicine (P.B., J.K.), Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic; and Department of Internal Medicine II (S.N.), Campus Grosshadern, University-Hospital of the Ludwig-Maximilians-University of Munich, 80539 Munich, Germany.
Karel
K
Pacak
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary; D008819:Mice, Nude; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D052117:Benzodioxoles; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007546:Isoquinolines; C553898:NSC 724998; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I