title: 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.
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Jong Kyu
authors.initials: JK
authors.lastname: Woo
authors.affiliation: National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: DongYun
authors.initials: D
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Seong-Hyeok
authors.initials: SH
authors.lastname: Park
authors.affiliation: Korea Institute of Science and Technology (KIST), Gangneung Institute, Gangneung-si, Gangwon-do, Republic of Korea.
authors.forename: Kyungsu
authors.initials: K
authors.lastname: Kang
authors.affiliation: Korea Institute of Science and Technology (KIST), Gangneung Institute, Gangneung-si, Gangwon-do, Republic of Korea.
authors.forename: Chu Won
authors.initials: CW
authors.lastname: Nho
authors.affiliation: Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.affiliation: National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea. eyeball@gachon.ac.kr.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Oh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism; D064107:Aurora Kinase B / Q000235:genetics* / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D018385:Centrosome / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D042822:Genomic Instability / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009281:Naphthalenes / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D052117:Benzodioxoles; D009281:Naphthalenes; C571067:daurinol; D049452:Green Fluorescent Proteins; D064096:Aurora Kinase A; D064107:Aurora Kinase B