Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host.
Anthracycline chemotherapeutic agents of the topoisomerase inhibitor family are widely used for the treatment of various tumors. Although targeted tumor tissues are generally situated in a hypoxic environment, the connection between efficacy of anthracycline agents and cellular hypoxia response has not been investigated in depth. Here, we report that doxorubicin (DXR) impairs the transcriptional response of the hypoxia-inducible factor (HIF) by inhibiting the binding of the HIF heterodimer to the consensus -RCGTG- enhancer element. This pleiotropic effect retarded migration of von Hippel-Lindau (VHL)-defective renal cell carcinoma and that of VHL-competent renal cell carcinoma in hypoxia. This effect was accompanied by a coordinated down-regulation of HIF target lysyl oxidase (LOX) family members LOX, LOX-like2 (LOXL2), and LOXL4. Furthermore, DXR suppressed HIF target genes in tumor xenografts, inhibited cardiac induction of HIF targets in rats with acute anemia, and impaired the angiogenic response in the isoproterenol-induced heart failure model, which may account for the clinical fragility of doxorubicin cardiomyopathy. Collectively, these findings highlight the impaired hypoxia response by anthracycline agents affecting both tumors and organs of the cancer host and offer a promising opportunity to develop HIF inhibitors using DXR as a chemical template.
Division for Health Service Promotion, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: tetsu-tky@umin.ac.jp.
Tetsuhiro
T
Tanaka
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Junna
J
Yamaguchi
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Kumi
K
Shoji
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: mnangaku-tky@umin.ac.jp.
Masaomi
M
Nangaku
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; D004317:Doxorubicin; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase