Daurinol Enhances the Efficacy of Radiotherapy in Lung Cancer via Suppression of Aurora Kinase A/B Expression

Abstract

The aurora kinases constitute one family of serine/threonine kinases whose activity is essential for mitotic progression. The aurora kinases are frequently upregulated in human cancers and are associated with sensitivity to chemotherapy in certain ones. In the present study, we investigated whether aurora kinases could be a target to overcome radioresistance or enhance the radiosensitivity of lung cancer. For that purpose, we determined the therapeutic potential of daurinol, an investigational topoisomerase inhibitor, alone and in combination with radiation, by observing its effect on aurora kinases. Daurinol decreased cell viability and proliferation in human colon and lung cancer cells. Gene expression in daurinol-treated human colon cancer cells was evaluated using RNA microarray. The mRNA expression of 18 genes involved in the mitotic spindle check point, including aurora kinase A (AURKA) and aurora kinase B (AURKB), was decreased in daurinol-treated human colon cancer cells as compared with vehicle-treated cells. As expected, radiation increased expression levels of AURKA and AURKB. This increase was effectively attenuated by siRNAs against AURKA and AURKB, which suppressed cell growth and increased apoptosis under radiation. Furthermore, the expression of AURKA and AURKB was suppressed by daurinol in the presence or absence of radiation in colon and lung cancer cells. Daurinol alone or in combination with radiation decreased lung cancer growth in xenograft mouse models. Our data clearly confirm the antitumor and radiosensitizing activity of daurinol in human lung cancer cells through the inhibition of AURKA and AURKB. Mol Cancer Ther; 14(7); 1693-704. Ó2015 AACR.

Aurora kinases: novel therapy targets in cancers

“…Besides, a group recently demonstrated that daurinol, a novel topoisomerase inhibitor, can inhibit the transcriptional activity of both AURKA and AURKB, which increased the radio-sensitivity of tumor cells in vivo and in vitro [150]. …”

Daurinol blocks breast and lung cancer metastasis and development by inhibition of focal adhesion kinase (FAK)

“…The development of novel therapeutic agents targeting cell motility is important for preventing tumor metastasis. Daurinol has been reported to have anti-cancer activities such as topoisomerase inhibition and suppression of aurora kinase expression [ 29 , 30 ]. However, the anti-metastatic effects of daurinol on cancer cells are still unclear.…”

“…Western blotting was conducted as previously described [ 30 , 57 ]. The primary antibodies included pAKT (Ser473), AKT, pFAK (Tyr925), pFAK (Tyr576), pFAK (Tyr397), FAK and tubulin were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA).…”

“…All cell lines were cultured at 37°C in the presence of 5% CO 2 . Cell proliferation was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as described previously [ 30 ]. Cells were plated at a density of about 3,000 cells/well in 96-well plates and incubated overnight.…”

“…Anti-cancer activities of daurinol against various human cancer cells have been reported. Recent studies have demonstrated its chemotherapeutic efficacy in colon [ 28 ], ovarian [ 29 ], and lung cancers [ 30 ]. In addition, daurinol has been reported to enhance radiation therapy efficacy in human lung cancers [ 30 ].…”