Yu-Jin Jung1, Eun Ha Lee1, Chang Gun Lee2, Ki-Jong Rhee2, Woo-Suk Jung1, Yongsoo Choi3, Cheol-Ho Pan4, Kyungsu Kang5. 1. Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea. 2. Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju 26493, Republic of Korea. 3. Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; Department of Biological Chemistry, University of Science and Technology (UST), Daejeon 34113, Republic of Korea. 4. Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; Department of Biological Chemistry, University of Science and Technology (UST), Daejeon 34113, Republic of Korea. Electronic address: panc@kist.re.kr. 5. Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; Department of Biological Chemistry, University of Science and Technology (UST), Daejeon 34113, Republic of Korea. Electronic address: kskang@kist.re.kr.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Selaginella tamariscina (P.Beauv.) Spring is a traditional medicinal plant used to treat various human diseases, including cancer, in Asia. The detailed molecular mechanism underlying the anti-cancer effects of this plant and the anti-cancer action of the combinatorial treatment of S. tamariscina and doxorubicin have not yet been investigated. AIM OF THE STUDY: We evaluated the inhibitory activity of S. tamariscina extract (STE) and its major compound, amentoflavone, on human aldo-keto reductase family 1B10 (AKR1B10), which is a detoxification enzyme involved in drug resistance, to evaluate their anti-cancer effects and their potential as adjuvant agents for doxorubicin cancer chemotherapy. MATERIALS AND METHODS: We tested the AKR1B10 inhibitory activity of STE and amentoflavone via an in vitro biochemical assay using recombinant human AKR1B10. We tested the anti-proliferative activity in A549, NCI-H460, SKOV-3, and MCF-7 human cancer cells, which contain different expression levels of AKR1B10, and determined the combination index to evaluate whether the addition of STE and amentoflavone is synergistic or antagonistic to the anti-cancer action of doxorubicin. We finally evaluated the in vivo anti-tumor effects of STE in a nude mouse xenograft model of A549 cells. RESULTS: STE and amentoflavone potently inhibited human AKR1B10 and synergistically increased the doxorubicin anti-proliferative effect in A549 and NCI-H460 human lung cancer cells that express a high level of AKR1B10 mRNA and protein. STE also significantly inhibited A549 tumor growth in animal experiments. CONCLUSION: Our results suggest that STE and amentoflavone could be potential anti-cancer agents that target AKR1B10 and might be candidate adjuvant agents to boost the anti-cancer effect of doxorubicin.
ETHNOPHARMACOLOGICAL RELEVANCE: Selaginella tamariscina (P.Beauv.) Spring is a traditional medicinal plant used to treat various human diseases, including cancer, in Asia. The detailed molecular mechanism underlying the anti-cancer effects of this plant and the anti-cancer action of the combinatorial treatment of S. tamariscina and doxorubicin have not yet been investigated. AIM OF THE STUDY: We evaluated the inhibitory activity of S. tamariscina extract (STE) and its major compound, amentoflavone, on humanaldo-keto reductase family 1B10 (AKR1B10), which is a detoxification enzyme involved in drug resistance, to evaluate their anti-cancer effects and their potential as adjuvant agents for doxorubicincancer chemotherapy. MATERIALS AND METHODS: We tested the AKR1B10 inhibitory activity of STE and amentoflavone via an in vitro biochemical assay using recombinant humanAKR1B10. We tested the anti-proliferative activity in A549, NCI-H460, SKOV-3, and MCF-7 humancancer cells, which contain different expression levels of AKR1B10, and determined the combination index to evaluate whether the addition of STE and amentoflavone is synergistic or antagonistic to the anti-cancer action of doxorubicin. We finally evaluated the in vivo anti-tumor effects of STE in a nude mouse xenograft model of A549 cells. RESULTS:STE and amentoflavone potently inhibited humanAKR1B10 and synergistically increased the doxorubicin anti-proliferative effect in A549 and NCI-H460 human lung cancer cells that express a high level of AKR1B10 mRNA and protein. STE also significantly inhibited A549 tumor growth in animal experiments. CONCLUSION: Our results suggest that STE and amentoflavone could be potential anti-cancer agents that target AKR1B10 and might be candidate adjuvant agents to boost the anti-cancer effect of doxorubicin.