HIF-1α modulation by topoisomerase inhibitors in non-small cell lung cancer cell lines
Open accessAbstract
Purpose This study was to investigate whether the topoisomerase (Top) I inhibitor topotecan and the Top II inhibitor etoposide could modulate the hypoxia-induced HIF-1alpha expression in non-small cell lung cancer (NSCLC) cell lines. Methods Hypoxic conditions were maintained in a humidified airtight anaerobic incubator flushed with a mixture of gas consisting of 1% O(2), 5% CO(2) and 94% N(2). The expressions of HIF-1alpha and Akt phosphorylation were measured by Western blotting or quantitative reverse transcription-polymerase chain reaction. Small interfering RNA treatment was done to inhibit the expressions of Top I and IIalpha. Constitutively active akt was expressed by transient transfection using pUSEamp(+)/myr Akt. Results The HIF-1alpha was increased and this peaked at 9 h in hypoxic conditions. Both topotecan and etoposide in a dose- and time-dependent manner inhibited the accumulation of hypoxia-induced HIF-1alpha protein. Interestingly, the daily addition of these drugs at a lower concentration could inhibit the HIF-1alpha expression more effectively than a single treatment, which shows that their effects are schedule-dependent. This down-regulation of HIF-1alpha was associated with proteosomal degradation and decreased Akt phosphorylation. Top I and Top IIalpha were required for the inhibitory effect of topotecan and etoposide, respectively. Conclusion Both Top I and II inhibitors could suppress the HIF-1alpha expression in a schedule-dependent manner, and this suggests that these drugs might be useful to overcome the therapeutic resistance induced by tumor hypoxia in NSCLC.
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Durable suppression of HIF-1α accumulation requires sustained target engagement.
“in vitro studies employing prolonged low-dose exposure suggest that durable suppression of HIF-1α accumulation requires sustained target engagement”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [316]
The Results (schedule-dependent modulation; page not supplied) report that daily low-dose addition of topotecan or etoposide inhibited HIF-1α expression more effectively than a single treatment. The Discussion says continuous suppression is desirable during cancer therapy. Neither passage establishes that sustained target engagement is required; the study compares dosing schedules, not the duration of target engagement. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDaily administration at low concentrations was more effective than a single high-dose treatment, suggesting a schedule-dependent component to HIF inhibition.
“Notably, daily administration at low concentrations was more effective than a single high-dose treatment, suggesting a schedule-dependent component to HIF inhibition.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [316]
These conditions were associated with diminished HIF-1α abundance alongside increased proteasomal degradation and attenuated Akt phosphorylation, indicating that HIF stability is modulated through signaling-dependent mechanisms.
“These conditions were associated with diminished HIF-1α abundance alongside increased proteasomal degradation and attenuated Akt phosphorylation, indicating that HIF stability is modulated through signaling-dependent mechanisms [316].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [316]
Hypoxia-induced HIF-1α accumulation is reduced by both topotecan and the topoisomerase II inhibitor etoposide in a manner dependent on dose and exposure time.
“Further evidence indicates that hypoxia-induced HIF-1α accumulation is reduced by both topotecan and the topoisomerase II inhibitor etoposide in a manner dependent on dose and exposure time.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [316]
The temporal dynamics of topoisomerase inhibition may critically influence HIF modulation and therapeutic outcome.
“These findings indicate that the temporal dynamics of topoisomerase inhibition may critically influence HIF modulation and therapeutic outcome [316].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [316]
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- Authors
- Choi, Y. J., Rho, J. K., Lee, S. J., Jang, W. S., Lee, S. S., Kim, C. H., & Lee, J. C.
- Affiliations
- Korea Institute of Radiological and Medical Sciences (KR)
- Corresponding author
- Lee, Jae Cheol
- Venue
- Journal of Cancer Research and Clinical Oncology
- Published
- 2009-01-15
- Volume
- 135
- Issue
- 8
- Pages
- 1047-1053
- ISSN
- 0084-5353 (ISSN-L)
- 0171-5216
- 1432-1335
- PMC
- PMC12160137
- OpenAlex
- W2054090900
- Cited by
- 25
- References
- 29
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Cancer Research and Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- HIF-1α, topotecan, etoposide, topoisomerase I inhibitor, topoisomerase II inhibitors, non-small cell lung cancer, tumor hypoxia, Akt phosphorylation, proteasomal degradation, treatment resistance, TOP2A
- MeSH terms
- Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, DNA Topoisomerases, Type II, DNA Topoisomerases, Type I, Enzyme Inhibitors, Etoposide, Humans, Lung Neoplasms, Topotecan, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Hypoxia-Inducible Factor 1, alpha Subunit, Topoisomerase I Inhibitors, Topoisomerase II Inhibitors
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