Inhibitory Effect of the Noncamptothecin Topoisomerase I Inhibitor LMP-400 on Female Mice Models and Human Pheochromocytoma Cells.

Abstract

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.

• Authors: Jan Schovanek, Petra Bullova, Yasin Tayem, Alessio Giubellino, Robert Wesley, Nikoletta Lendvai, Svenja Nölting, Juraj Kopacek, Zdenek Frysak, Yves Pommier, Shivaani Kummar, Karel Pacak
• Journal: Endocrinology (Endocrinology) Vol. 156 Issue 11 Pg. 4094-104 (Nov 2015) ISSN: 1945-7170 [Electronic] United States
• PMID: 26267380 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Benzodioxoles
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoquinolines
• NSC 724998
• Topoisomerase I Inhibitors
• DNA Topoisomerases, Type I

Topics

• Adrenal Gland Neoplasms (drug therapy, enzymology, pathology)
• Animals
• Antineoplastic Agents (pharmacology)
• Benzodioxoles (administration & dosage, pharmacology)
• Blotting, Western
• Cell Hypoxia
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type I (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Isoquinolines (administration & dosage, pharmacology)
• Liver Neoplasms (drug therapy, enzymology, secondary)
• Lung Neoplasms (drug therapy, enzymology, secondary)
• Mice, Nude
• PC12 Cells
• Pheochromocytoma (drug therapy, enzymology, pathology)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Topoisomerase I Inhibitors (administration & dosage, pharmacology)
• Tumor Cells, Cultured