Triptolide, a Chinese Herbal Extract, Enhances Drug Sensitivity of Resistant Myeloid Leukemia Cell Lines Through Downregulation of HIF-1α and Nrf2

Abstract

Aim: To explore whether triptolide (TPL) can enhance drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1α and Nrf2. Materials & methods: HL60/A and K562/G cells were subjected to different treatments and thereafter an methyl thiazole tetrazolium bromide assay, flow cytometry, western blot and real-time PCR were used to determine IC₅₀, apoptotic status and expression of Nrf2, HIF-1α and their target genes. Results: Doxorubicin- or imatinib-induced apoptosis was enhanced when anticancer agents were used in combination with TPL. When combined with TPL, both doxorubicin and imatinib downregulate Nrf2 and HIF-1α expression at protein and mRNA levels. Genes downstream of Nrf2, for example, NQO1, GSR and HO-1, as well as target genes of HIF-1α, for example, BNIP3, VEGF and CAIX are also downregulated at the mRNA level. Conclusion: TPL is able to enhance drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1α and Nrf2.

Original submitted 7 January 2013; Revision submitted 20 June 2013

KEYWORDS::

• drug resistance
• HIF-1α
• Nrf2
• triptolide

Financial & competing interests disclosure

This work was financially supported by National Nature Science Foundation of China, PR China (No. 81070425) and the technology program of Guangdong Province, PR China (No. 2011B031800063). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was financially supported by National Nature Science Foundation of China, PR China (No. 81070425) and the technology program of Guangdong Province, PR China (No. 2011B031800063). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.