DOI QR코드

DOI QR Code

Anticancer Activity of Novel Daphnane Diterpenoids from Daphne genkwa through Cell-Cycle Arrest and Suppression of Akt/STAT/Src Signalings in Human Lung Cancer Cells

  • 투고 : 2012.10.26
  • 심사 : 2012.11.12
  • 발행 : 2012.11.30

초록

Although the immense efforts have been made for cancer prevention, early diagnosis, and treatment, cancer morbidity and mortality has not been decreased during last forty years. Especially, lung cancer is top-ranked in cancer-associated human death. Therefore, effective strategy is strongly required for the management of lung cancer. In the present study, we found that novel daphnane diterpenoids, yuanhualine (YL), yuanhuahine (YH) and yuanhuagine (YG) isolated from the flower of Daphne genkwa (Thymelaeaceae), exhibited potent anti-proliferative activities against human lung A549 cells with the $IC_{50}$ values of 7.0, 15.2 and 24.7 nM, respectively. Flow cytometric analysis revealed that the daphnane diterpenoids induced cell-cycle arrest in the G0/G1 as well as G2/M phase in A549 cells. The cell-cycle arrests were well correlated with the expression of checkpoint proteins including the up-regulation of cyclin-dependent kinase inhibitor p21 and p53 and down-regulation of cyclin A, cyclin B1, cyclin E, cyclin dependent kinase 4, cdc2, phosphorylation of Rb and cMyc expression. In the analysis of signal transduction molecules, the daphnane diterpenoids suppressed the activation of Akt, STAT3 and Src in human lung cancer cells. The daphnane diterpenoids also exerted the potent anti-proliferative activity against anticancer-drug resistant cancer cells including gemcitabine-resistant A549, gefitinib-, erlotinib-resistant H292 cells. Synergistic effects in the growth inhibition were also observed when yuanhualine was combined with gemcitabine, gefitinib or erlotinib in A549 cells. Taken together, these findings suggest that the novel daphnane diterpenoids might provide lead candidates for the development of therapeutic agents for human lung cancers.

키워드

참고문헌

  1. Chang, A. (2011) Chemotherapy, chemoresistance and changing treatment landscape for NSCLC. Lung Cancer 71, 3-10. https://doi.org/10.1016/j.lungcan.2010.08.022
  2. Chou, T. C. (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621-681. https://doi.org/10.1124/pr.58.3.10
  3. He, W., Cik, M., Appendino, G., Puyvelde, L. V., Leysen, J. E. and De Kimpe, N. (2002) Daphnane-type diterpene orthoesters and their biological activities. Mini Rev. Med. Chem. 2, 185-200. https://doi.org/10.2174/1389557024605492
  4. Hong, J. Y., Chung, H. J., Lee, H. J., Park, H. J. and Lee, S. K. (2011) Growth inhibition of human lung cancer cells via down-regulation of epidermal growth factor receptor signaling by yuanhuadine, a daphnane diterpene from Daphne genkwa. J. Nat. Prod. 74, 2102-2108. https://doi.org/10.1021/np2003512
  5. Hong, J. Y., Nam, J. W., Seo, E. K. and Lee, S. K. (2010) Daphnane diterpene esters with anti-proliferative activities against human lung cancer cells from Daphne genkwa. Chem. Pharm. Bull. 58, 234-237. https://doi.org/10.1248/cpb.58.234
  6. Janmaat, M. L., Rodriguez, J. A., Gallegos-Ruiz, M., Kruyt, F. A. and Giaccone, G. (2006) Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int. J. Cancer 118, 209-214. https://doi.org/10.1002/ijc.21290
  7. Johnson, D. G. and Walker, C. L. (1999) Cyclins and cell cycle checkpoints. Annu. Rev. Pharmacol. Toxicol. 39, 295-312. https://doi.org/10.1146/annurev.pharmtox.39.1.295
  8. Lee, S. K., Cui, B., Mehta, R. R., Kinghorn, A. D. and Pezzuto, J. M. (1998) Cytostatic mechanism and antitumor potential of novel 1H-cyclopental[b]benzofuran lignans isolated from Aglaia elliptica.Chem. Biol. Interact. 115, 215-228. https://doi.org/10.1016/S0009-2797(98)00073-8
  9. Liang, J. and Slingerland, J. M. (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2, 339-345.
  10. Mann, J. (2002) Natural products in cancer chemotherapy: past, present and future. Nat. Rev. Cancer 2, 143-148. https://doi.org/10.1038/nrc723
  11. Park, B. Y., Min, B. S., Ahn, K. S., Kwon, O. K., Joung, H., Bae, K. H., Lee, H. K. and Oh, S. R. (2007) Daphnane diterpene esters isolated from flower buds of Daphne genkwa induce apoptosis in human myelocytic HL-60 cells and suppress tumor growth in Lewis lung carcinoma (LLC)-inoculated mouse model. J. Ethnopharmacol. 111, 496-503. https://doi.org/10.1016/j.jep.2006.12.023
  12. Pfister, D. G., Johnson, D. H., Azzoli, C. G., Sause, W., Smith, T. J., Baker, S. Jr., Olak, J., Stover, D., Strawn, J. R. and Turrisi, A. T. (2004) American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Update. J. Clin. Oncol. 22, 330-353.
  13. Seve, P. and Dumontet, C. (2005) Chemoresistance in non-small cell lung cancer. Curr. Med. Chem. Anticancer Agents 5, 73-88. https://doi.org/10.2174/1568011053352604
  14. Shapiro, G. I. (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770-1783 https://doi.org/10.1200/JCO.2005.03.7689
  15. Shepherd, F. A. (2003) Second-line chemotherapy from non-small lung cancer. Expert Rev. Anticancer Ther. 3, 435-442. https://doi.org/10.1586/14737140.3.4.435
  16. Siegel, R., Naishadham, D. and Jemal, A. (2012) Cancer statistics, 2012. CA Cancer J. Clin. 62, 10-29. https://doi.org/10.3322/caac.20138
  17. Skehan, P., Storeng, R., Scudiero, D. Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenney, S. and Boyd, M. R. (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107-1112. https://doi.org/10.1093/jnci/82.13.1107
  18. Smits, V. A. and Meedema, R. H. (2001) Checking out the G(2)/M transition. Biochim. Biophys. Acta. 28, 1-12.
  19. Wullschleger, S., Loewith, R. and Hall, M. N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484. https://doi.org/10.1016/j.cell.2006.01.016
  20. Zhan, Z. J., Fan, C. Q., Ding , J. and Yue, J. M. (2005) Novel diterpenoids with potent inhibitory activity against endothelium cell HMEC and cytotoxic activities from a well-known TCM plant Daphne genkwa. Bioorg. Med. Chem. 13, 645-655. https://doi.org/10.1016/j.bmc.2004.10.054
  21. Zhang, S., Li, X., Zhang, F., Yang, P., Gao, X. and Song, Q. (2006) Preparation of yuanhuacine and relative daphne diterpene esters from Daphne genkwa and structure-activity relationship of potent inhibitory activity against DNA topoisomerase I. Bioorg. Med. Chem. 14, 3888-3895. https://doi.org/10.1016/j.bmc.2006.01.055

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  1. Toxicity of daphnane-type diterpenoids from Genkwa Flos and their pharmacokinetic profile in rat vol.21, pp.1, 2013, https://doi.org/10.1016/j.phymed.2013.06.012
  2. Genkwadaphnin Induces IFN-γ via PKD1/NF-κB/STAT1 Dependent Pathway in NK-92 Cells vol.9, pp.12, 2014, https://doi.org/10.1371/journal.pone.0115146
  3. AP-1/IRF-3 Targeted Anti-Inflammatory Activity of Andrographolide Isolated fromAndrographis paniculata vol.2013, 2013, https://doi.org/10.1155/2013/210736
  4. Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway vol.37, pp.7, 2016, https://doi.org/10.1007/s13277-016-4864-x
  5. Extracellular Signal-Regulated Kinase Is a Direct Target of the Anti-Inflammatory Compound Amentoflavone Derived fromTorreya nucifera vol.2013, 2013, https://doi.org/10.1155/2013/761506
  6. Elucidating high-dimensional cancer hallmark annotation via enriched ontology vol.73, 2017, https://doi.org/10.1016/j.jbi.2017.07.011
  7. A new highly oxygenated daphnane diterpene esters from the flower buds ofDaphne genkwa vol.29, pp.20, 2015, https://doi.org/10.1080/14786419.2015.1009459
  8. Yuanhuapine-induced intestinal and hepatotoxicity were correlated with disturbance of amino acids, lipids, carbohydrate metabolism and gut microflora function: A rat urine metabonomic study vol.1026, 2016, https://doi.org/10.1016/j.jchromb.2015.08.024
  9. Fisetin induces apoptosis in human nonsmall lung cancer cells via a mitochondria-mediated pathway vol.51, pp.3, 2015, https://doi.org/10.1007/s11626-014-9830-6
  10. Evaluation of subchronic (13week) toxicity and genotoxicity potential of vinegar-processed Genkwa Flos vol.72, pp.2, 2015, https://doi.org/10.1016/j.yrtph.2015.04.008
  11. Targeting antitumor effect of rhTNF-α fusion protein mediated by matrix metalloproteinase-2 vol.33, pp.2, 2015, https://doi.org/10.3892/or.2014.3616
  12. Antimetastatic Effect of Halichondramide, a Trisoxazole Macrolide from the Marine Sponge Chondrosia corticata, on Human Prostate Cancer Cells via Modulation of Epithelial-to-Mesenchymal Transition vol.11, pp.7, 2013, https://doi.org/10.3390/md11072472
  13. Discovery of quinolinone derivatives as potent FLT3 inhibitors vol.445, pp.3, 2014, https://doi.org/10.1016/j.bbrc.2014.02.029
  14. Shikonin induces cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression vol.151, pp.3, 2014, https://doi.org/10.1016/j.jep.2013.11.055
  15. Ohmyungsamycins A and B: Cytotoxic and Antimicrobial Cyclic Peptides Produced byStreptomycessp. from a Volcanic Island vol.78, pp.24, 2013, https://doi.org/10.1021/jo401974g
  16. Akt regulation of Aven contributes to the sensitivity of cancer cells to chemotherapeutic agents vol.11, pp.5, 2015, https://doi.org/10.3892/mmr.2015.3158
  17. Cryptotanshinone inhibits lung tumor growth by increasing CD4+ T cell cytotoxicity through activation of the JAK2/STAT4 pathway vol.12, pp.5, 2016, https://doi.org/10.3892/ol.2016.5123
  18. Plants from The Genus Daphne: A Review of its Traditional Uses, Phytochemistry, Biological and Pharmacological Activity vol.18, pp.1, 2017, https://doi.org/10.1515/sjecr-2016-0024
  19. Screening for selective anticancer activity of plants from Grazalema Natural Park, Spain pp.1478-6427, 2018, https://doi.org/10.1080/14786419.2018.1480620
  20. Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells vol.15, pp.2, 2012, https://doi.org/10.3892/etm.2017.5591
  21. AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells vol.10, pp.5, 2019, https://doi.org/10.1038/s41419-019-1601-6
  22. A Review on Daphnane-Type Diterpenoids and Their Bioactive Studies vol.24, pp.9, 2012, https://doi.org/10.3390/molecules24091842
  23. Advances in plant-derived natural products for antitumor immunotherapy vol.44, pp.11, 2012, https://doi.org/10.1007/s12272-021-01355-1
  24. Phytochemistry and Pharmacological Activities of the Diterpenoids from the Genus Daphne vol.26, pp.21, 2012, https://doi.org/10.3390/molecules26216598