Antitumor effect of the selective hypoxia-inducible factor-1 inhibitors echinomycin and PX-478 on uterine fibroids

Linlin Xu, Hiroshi Ishikawa, Yanruo Zhou, Tatsuya Kobayashi, Makio Shozu

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: To investigate the antitumor effects of the selective hypoxia-inducible factor-1 (HIF-1) inhibitors echinomycin and PX-478 on uterine fibroids. Design: Experimental study using in vitro primary culture systems and an in vivo mouse xenograft model. Setting: Academic university center. Patient(s): Women with uterine fibroids who underwent hysterectomy or myomectomy. Intervention(s): Administration of the selective HIF-1 inhibitors echinomycin and PX-478 to the media of the primary cultured uterine fibroid cells and to nonobese diabetic/severe combined immunodeficient mice bearing fibroid xenografts consisting of the primary cultured fibroid cells and type Ⅰ collagen gels beneath the kidney capsule. Main Outcome Measure(s): Cell proliferation was measured by Cell Counting Kit-8 assay. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and by measuring caspase 3 and 7 activities. The xenografts were evaluated by gross appearance, surface area, and histology. The Ki-67 index was measured to evaluate proliferation of the xenografts. Result(s): Both echinomycin and PX-478 inhibited cell proliferation and induced apoptosis in fibroid cells cultured under hypoxia and normoxia. Enlargement of the fibroid xenografts was significantly attenuated. The Ki-67 index significantly decreased after the administration of the HIF-1 inhibitors in the xenograft model. Eight of 27 xenografts treated with the HIF-1 inhibitors contained calcification and hyalinizing components from 3 days after the grafting to 2 weeks, suggesting that the HIF-inhibitors induce degeneration of the fibroid xenografts. Conclusion(s): The selective HIF-1 inhibitors echinomycin and PX-478 show antitumor effects against uterine fibroids both in vitro and in vivo. These findings support the potential use of HIF-1 inhibitors for the treatment of uterine fibroids.

Original languageEnglish
Pages (from-to)187-196
Number of pages10
JournalF and S Science
Volume3
Issue number2
DOIs
Publication statusPublished - 05-2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Reproductive Medicine
  • Embryology

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