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HIF-1α modulation by topoisomerase inhibitors in non-small cell lung cancer cell lines

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Abstract

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-1α 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% O2, 5% CO2 and 94% N2. The expressions of HIF-1α 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 IIα. Constitutively active akt was expressed by transient transfection using pUSEamp(+)/myr Akt.

Results

The HIF-1α 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-1α protein. Interestingly, the daily addition of these drugs at a lower concentration could inhibit the HIF-1α expression more effectively than a single treatment, which shows that their effects are schedule-dependent. This down-regulation of HIF-1α was associated with proteosomal degradation and decreased Akt phosphorylation. Top I and Top IIα were required for the inhibitory effect of topotecan and etoposide, respectively.

Conclusion

Both Top I and II inhibitors could suppress the HIF-1α 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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Authors and Affiliations

  1. Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, 215-4, Gongneung-dong, Nowon-gu, Seoul, 139-706, Korea

    Yun Jung Choi, Jin Kyung Rho, Cheol Hyeon Kim & Jae Cheol Lee

  2. Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Science, 215-4, Gongneung-dong, Nowon-gu, Seoul, 139-706, Korea

    Sun Joo Lee, Won Seok Jang & Seung Sook Lee

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  1. Yun Jung Choi
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  2. Jin Kyung Rho
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  3. Sun Joo Lee
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  4. Won Seok Jang
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  5. Seung Sook Lee
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  6. Cheol Hyeon Kim
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  7. Jae Cheol Lee
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Correspondence to Jae Cheol Lee.

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Choi, Y.J., Rho, J.K., Lee, S.J. et al. HIF-1α modulation by topoisomerase inhibitors in non-small cell lung cancer cell lines. J Cancer Res Clin Oncol 135, 1047–1053 (2009). https://doi.org/10.1007/s00432-009-0543-2

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  • DOI: https://doi.org/10.1007/s00432-009-0543-2

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