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Mechanistic Studies on the Anti-tumor Effects of Indirubin-3‘-oxime on Human Neuroblastoma Cells

Mechanistic Studies on the Anti-tumor Effects of Indirubin-3‘-oxime on Human Neuroblastoma Cells. K.N. Leung Food and Nutritional Sciences and Biochemistry Programmes School of Life Sciences The Chinese University of Hong Kong. 5 th Asia-Pacific Summit on Cancer Therapy

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Mechanistic Studies on the Anti-tumor Effects of Indirubin-3‘-oxime on Human Neuroblastoma Cells

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  1. Mechanistic Studies on the Anti-tumorEffects of Indirubin-3‘-oxime on Human Neuroblastoma Cells K.N. Leung Food and Nutritional Sciences and Biochemistry Programmes School of Life Sciences The Chinese University of Hong Kong 5th Asia-Pacific Summit on Cancer Therapy July 20-22, 2015 Brisbane, Australia

  2. Contents Introduction Human Neuroblastoma (NB) andIndirubin-3‘-oxime (I3M) Anti-tumor Effects of Indirubin-3‘-oxime on Human Neuroblastoma Cells Mechanistic Studies and Molecular Action Mechanisms of Indirubin-3‘-oxime Conclusions and Future Perspectives

  3. An extracranial tumor derived from primitive cells of thesympathetic nervous system The most common and deadly solid tumor of childhood Accounts for 8 - 10% of all childhood cancers and ~ 15% of all childhood cancer-related deaths Bones around the eyes or orbits Chest Abdomen What is Neuroblastoma? Symptoms：

  4. Etiology of Neuroblastoma Protective factors: Risk factors: • Occupation • Smoking • Alcohol consumption • Use of hormones and fertility drugs • Maternal use of hair dye • Use of medicinal drugs during pregnancy pregnancy • Folic acidsupplements • Vitamin supplements

  5. Molecular Pathogenesis of Neuroblastoma • N-myc amplification state: a key factor in the genesis of human neuroblastoma • Chromosomal abnormalities • Mutations in the PHOX2BandALK genes • Disruption of cell division cycle, apoptosis and other signaling pathways

  6. Treatment of Neuroblastoma Intermediate risk Low risk High risk Cure rate >90% 70% - 90% ~30% • Multimodality therapy: • Chemotherapy • Surgery • Radiation therapy • Stem cell transplantation • Differentiation therapy • Immunotherapy Surgery alone Surgery and Chemotherapy

  7. Indirubin-3'-oxime (I3M) (A cell permeable derivative of indirubin ) Indirubin is an indole alkaloid isolated from the dried roots (Banlangen) of medicinal indigo plants Polygonum tinctorium Isatis indigotica Isatis tinctoria Strobilanthes cusia

  8. Indirubin-3'-oxime Biological and Pharmacological Activities of Indirubin-3'-oxime (I3M) Inhibitor of CDKs and GSK-3b Anti-inflammatory activity Anti-angiogenic activity Anti-viral activity Anti-tumor activity

  9. Indirubin-3'-oxime Inhibited the Growth of LA-N-1, SK-N-DZ and SH-SY5Y Human Neuroblastoma Cells MTT assay

  10. Effect of I3M on the Viability of Normal Cells

  11. I3M Failed to Induce Apoptosis in LA-N-1 cells ** P< 0.01

  12. I3M Arrested LA-N-1 Cells at G0/G1 Phase ** P< 0.01; *** P< 0.001

  13. Mitochondria and Cell Cycle In HeLa cells：human cervical carcinoma Induces cell cycle arrest at G1 phase hMTERF4 Promotes cell proliferation In Drosophila ATP production Mutation in the cytochrome oxidase subunit Va Cell cycle arrest at G1 phase Reactive oxygen species Pdsw, a subunit of mitochondrial complex I Blocked in G1-S transition Cyclin E CDKI p27Kip1

  14. ERRs and PGC-1s (Sonoda J et al. 2008) • Estrogen-related receptor  and  (ERR and ERR) are • constitutively active nuclear hormone receptors. • They are thought to regulate mitochondrial biogenesis and • oxidative phosphorylation together with their coactivators • peroxisome proliferator-activated receptor  coactivator-1 • and -1 (PGC-1 and PGC-1).

  15. I3M Selectively Reduced Mitochondrial Regulators (ERRg and PGC-1b) in LA-N-1 cells ** P< 0.01; *** P< 0.001

  16. I3M Reduced Mitochondrial Regulated Gene Expression in LA-N-1 cells Mito. Transcription Factor A Tfam SOD1 ATP5b SOD2 ATP synthase Superoxide dismutase 2 ** P< 0.01 *** P< 0.001

  17. I3M Caused Mitochondrial Dysfunction in LA-N-1 Cells Mitochondrial Membrane Potential Mitochondrial ROS Level Mitochondrial Mass ** P< 0.01 *** P< 0.001

  18. I3M effects on LA-N-1 cells ERRgPGC-1b Mitochondrial mass Mitochondrial membrane potential Reactive oxygen species Cell growth inhibition CDK2, Cyclin E p27Kip1 Cell cycle arrest at G0/G1 phase

  19. Anti-angiogenic Activities of I3M on Human Microvascular Endothelial HMEC-1 cells I3M p-VEGFR2 Angiogenic factors Ang-1 and MMP2 p-AKT, p-GSK3β p-MEK1/2, p-ERK1/2 Endothelial cell proliferation, migration, and tube formation Angiogenesis

  20. I3M Reduced the Matrigel Plug In vivo Angiogenesis *** p< 0.001

  21. Conclusions and Future Perspectives • Indirubin-3’-oxime (I3M) is a potential therapeutic agent for high risk neuroblastoma with N-myc amplification • I3M possesses anti-angiogenic activities, both in vitro and in vivo • In vivo studies of I3M in animal models (anti-tumor efficacy and acute and chronic toxicities) • Any synergistic effects when used in combinations with other chemotherapeutic drugs or natural products

  22. Acknowledgements Dr. Selena LIAO Xuemei (CUHK) Dr. Simon LIU Wai-nam (CUHK) Ms. Ada KONG Lai-ping (CUHK) Prof. N.K. MAK (HKBU) Prof. N.S. WONG (HKBU)

  23. Thank you for your attention!

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