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

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-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.

• Authors: Yun Jung Choi, Jin Kyung Rho, Sun Joo Lee, Won Seok Jang, Seung Sook Lee, Cheol Hyeon Kim, Jae Cheol Lee
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 135 Issue 8 Pg. 1047-53 (Aug 2009) ISSN: 1432-1335 [Electronic] Germany
• PMID: 19148680 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Etoposide
• Topotecan
• Proto-Oncogene Proteins c-akt
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, metabolism)
• Cell Line, Tumor
• DNA Topoisomerases, Type I (metabolism)
• DNA Topoisomerases, Type II (metabolism)
• Enzyme Inhibitors (pharmacology)
• Etoposide (pharmacology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Lung Neoplasms (drug therapy, enzymology, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Topotecan (pharmacology)