Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • 2024-08
  • 2024-09
  • 2024-10
  • 2024-11
  • 2024-12
  • br HIF Blockade in AA Therapy In

    2024-11-06


    HIF-α Blockade in AA Therapy In lieu of the evidence supporting a central role for HIF-α signaling in tumor angiogenesis and CC pathobiology, significant efforts have focused on the discovery of small-molecule HIF-α inhibitors (for exhaustive compendia, see [28,44,45]). In brief, inhibitors vary in specificity according to the particular molecular mechanism enacting decreased HIF-α levels, wherein the HIF-α:HIF-1ß dimerization inhibitors and antisense oligonucleotides perhaps hold the most potential for specificity. For a summary of the main drug classes showing HIF-α inhibitory activity, see Table 1. Of particular clinical interest for AA cancer therapy is the usage of topoisomerase inhibitors, recently shown to inhibit HIF-α. Here, we discuss improved nanoparticle formulations and structurally novel drugs with enhanced selectivity for HIF-1α (or -2α). In particular, we detail recent preclinical results in which AA therapy was combined with topoisomerase inhibitors in the context of HIF-α levels and LDM administration (Table 2).
    Topoisomerase Inhibitors Topoisomerase-1 (Topo-1) activity induces DNA single-strand breaks, relieving torsional tension during DNA repair, transcription, and replication [46]. Most topoisomerase inhibitors are derivatives of the alkaloid camptothecin, wherein topotecan (NSC609699) constitutes a prototypical inhibitor with significant cytotoxic effects against proliferating CCs [47]. Consistently, DNA replication is required for topotecan to trigger S-phase cytotoxicity and G2-M phase Otilonium Bromide arrest in CCs. Mechanistically, topotecan binds to Topo-1/DNA cleavage complexes, preventing the advancement of replication forks and DNA religation, leading to double-strand breaks. High-throughput screenings identified topotecan as a novel HIF-α inhibitor [48]. Topotecan-mediated HIF-1α inhibition occurred at the protein level independently of proteasomal degradation, DNA replication, or PI3K→mTOR signaling and resulted in VEGF-A transcription blockade [28]. By contrast, treatment with the RNA transcription inhibitor actinomycin-D reversed the effect of topotecan upon hypoxic HIF-1α protein accumulation [28]. Interestingly, Topo-1 silencing did not affect topotecan-mediated HIF-1α inhibition, suggesting a unique Topo-1-independent mechanism for HIF-1α blockade [49]. Recent work suggests that the AA effect of topotecan upon EC proliferation is enhanced by the usage of a LDM schedule (Box 3), as opposed to MTD chemotherapy [49,50]. This improved efficacy of LDM over MTD is due to the rapid HIF-α protein turnover in CCs (i.e., constantly synthesized and degraded after ≈15min under non-hypoxic conditions) combined with the short half-life (≈2.8h) of topotecan, thus explaining the requirement for continuous drug supply. These observations are further supported by in vitro data showing that HIF-1α inhibition is reversed upon topotecan withdrawal from the media of hypoxic CCs as early as 2h. Indeed, daily LDM topotecan administration is more effective in achieving sustained HIF-1α inhibition than a single higher dose in hypoxic glioma cells [28,50]. Furthermore, LDM topotecan decreases HIF-1α-dependent target gene transactivation, vascularization, xenograft, and in vitro growth of glioma and ovarian CCs [28,49]. Taken together, these results suggest that LDM topotecan efficaciously blocks the enhancement of HIF-1α signaling observed after AA therapy. Noteworthy, the results of a Phase 1 clinical trial testing the effect of topotecan on refractory advanced solid neoplasms overexpressing HIF-1α are pending (NCT00117013). LDM topotecan administration combined with the RTKI pazopanib (blocking c-KIT, FGFR, PDGFR, and VEGFRs) or sunitinib in triple-negative breast cancers significantly decreased HIF-1α and the multidrug resistance transporter ABCG2, leading to increased intracellular topotecan concentrations and enhanced antitumor efficacy [50]. Of note, ABCG2 overexpression induced resistance to topotecan in ovarian CCs in vitro, while ABCG2 is a direct HIF-1α target [50–52].