title: Mitoxantrone inhibits HIF-1α expression in a topoisomerase II-independent pathway.
abstract: OBJECTIVE
  Solid tumors encounter a growth-limiting hypoxic microenvironment as they develop. Hypoxia-inducible factors (HIF) play important roles in hypoxia-associated tumor development and therapeutic resistance. Targeting the HIF pathway (especially HIF-1α) represents a promising cancer treatment strategy. Here, we report a novel class of HIF-1α inhibitors and the possible molecular basis of inhibition.
  
  
  METHODS
  We analyzed the inhibitory effects of clinically used topoisomerase II (TOP2)-targeting drugs on HIF-1α expression with a primary focus on mitoxantrone. The potential role of TOP2 in mitoxantrone-inhibited HIF-1α expression was studied using pharmacologic inhibition, a knockdown approach, and TOP2 mutant cells. Moreover, involvement of mitoxantrone in proteasome-mediated degradation, transcription, and translation of HIF-1α was examined.
  
  
  RESULTS
  The TOP2-targeting mitoxantrone, but neither doxorubicin nor etoposide (VP-16), strongly inhibited HIF-1α expression under hypoxic conditions in a dose- and time-dependent manner. Surprisingly, the mitoxantrone-mediated inhibition of HIF-1α expression was largely independent of two TOP2 isozymes, proteasomal degradation, and transcription. Furthermore, mitoxantrone inhibited HIF-1α expression and function in a similar fashion as cycloheximide, suggesting that mitoxantrone might inhibit HIF-1α via a blockage at its translation step. In vitro translation experiments using HIF-1α mRNA further confirmed inhibition of HIF-1α translation by mitoxantrone. Interestingly, levels of the polysome-bound HIF-1α and VEGF-A mRNA were elevated and decreased after mitoxantrone treatment, respectively.
  
  
  CONCLUSIONS
  We have identified the TOP2-targeting compound, mitoxantrone, as an HIF-1α inhibitor possibly through a translation inhibition mechanism, suggesting the possibility of an additional anticancer activity for mitoxantrone.
authors.affiliation: Department and Graduate Institute of Microbiology, College of Medicine, and Center for Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Yng-Miin
authors.initials: YM
authors.lastname: Toh
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism*; D008942:Mitoxantrone / Q000494:pharmacology*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D008942:Mitoxantrone; D046988:Proteasome Endopeptidase Complex; D004250:DNA Topoisomerases, Type II