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Shen Han-Ming Department of COFM Yong Loo Lin School of Medicine National University of Singapore

Luteolin, a Major Flavonoid from Chrysanthemum, as a Chemosensitizer to Apoptosis in Human Cancer Cells. Shen Han-Ming Department of COFM Yong Loo Lin School of Medicine National University of Singapore. Scientific name:. Chrysanthemum morifolium Ramat. Main Production place:.

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Shen Han-Ming Department of COFM Yong Loo Lin School of Medicine National University of Singapore

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  1. Luteolin, a Major Flavonoid from Chrysanthemum, as a Chemosensitizer to Apoptosis in Human Cancer Cells Shen Han-Ming Department of COFM Yong Loo Lin School of Medicine National University of Singapore

  2. Scientific name: • Chrysanthemum morifolium Ramat. Main Production place: • Eastern China Main usage: • TCM • Beverage

  3. Luteolin • Known Bio-function of Luteolin: • Anti-inflammatory: inhibition of NF-kB • Antioxidant • Cytotoxic (high concentration)

  4. Section I: Luteolin enhances TNF-induced apoptosis in cancer cells Section II: Luteolin sensitizes TRAIL-induced apoptosis in cancer cells Section III: Luteolin enhances cisplatin-induced cell death both in vitro and in vivo

  5. Tumor Necrosis Factor (TNF) • TNF is a proinflammatory cytokine with critical roles in a wide range of cellular functions • TNFR1 mediates several downstream signaling pathways: • (i) caspase cascade: apoptotic • (ii) NF-B: anti-apoptotic • 3. Limited application of TNF in cancer therapy

  6. Apoptosis luteolin A20 cIAP1 Shi RX et al., Oncogene 2004

  7. TNF-Related Apoptosis-Inducing Ligand (TRAIL) • Member of the TNF gene superfamily • Induces apoptosis through engagement of death receptors (DR4/DR5) • TRAIL selectively induces apoptosis in many transformed cells but not in normal cells, thus with greater potential as a potential tumor-specific cancer therapeutic • One of the common problems in TRAIL therapy is resistance

  8. Luteolin down-regulates XIAP protein level through promotion of XIAP ubiquitination and proteasomaldegradation to remove the blockage of apoptosis in TRAIL-treated human cancer cells Shi RX et al., Cancer Res 2005

  9. Luteolin enhances cisplatin-induced apoptosis in human cancer cells Cisplatin - - 2 5 10 2 5 10 Luteolin - + - - - + + +

  10. Luteolin enhances cisplatin-induced caspase 3 activation and nuclear condensation control Luteolin control Cisplatin Luteolin - + - + + Cisplatin - - + + + Z-VAD-fmk - - - - + Pro-Caspase 3 Cleaved Caspase 3 PARP Tubulin

  11. 3 h 6 h 12 h 18 h Luteolin - + - + + - + + - + + - + Cisplatin - - + + - + + - + + - + + p53 Tubulin Luteolin and cisplatin up-regulated p53 protein level in a time-dependent manner

  12. Luteolin and cisplatin induced apoptosis in p53-wild type cells but not in p53-mutant cancer cells Control Lu+Cisplatin HepG2 Hep3B HCT116 HT29

  13. Scrambled siRNA p53 siRNA Lu+Cisplatin - + - + p53 Tub Control Lu+Cisplatin p53 knockdown blocks the apoptosis induced by luteolin and cisplatin

  14. Luteolin stabilizes p53 protein level CHX (min) 0 15 30 60 120 240 p53 DMSO Tubulin p53 Luteolin Tubulin

  15. Luteolin induces specific p53 protein phosphorylation Luteolin p-p53-Thr81 p-p53-ser15 p53 MDM2 Luteolin p-p53-ser392 p53 Tubulin

  16. Luteolin activates JNK but not p38 Luteolin p-JNK JNK Luteolin p-p38 p38

  17. SP600125, a specific JNK inhibitor, blocks luteolin-induced p53 protein phosphorylation p-JNK JNK p-p53-Thr81 p-p53-ser15 p53 Tubulin

  18. Suppression of JNK activation protects cell death induced by Lu+cisplatin CTRL Luteolin SP pDsRed+ HA-JNKK1(DN)+ HA-JNKK2(DN) pDsRed+ pcDNA E CTRL Luteolin+ Cisplatin SP+Luteolin +Cisplatin Cisplatin Luteolin+ Cisplatin

  19. Luteolin inhibits p53 ubiquitination via JNK activation MG132 SP600125 Luteolin 220kD IP:p53 IB: ubiquitin 97kD 66kD 55kD 1% input WB:p53

  20. Significant reduction of tumor size by luteolin+cisplatin in a nude mice xenograft model CTRL Cisplatin Luteolin Luteolin+ Cisplatin CTRL Cisplatin Luteolin Luteolin+ Cisplatin

  21. Significant accumulation of p53 protein in tumor cells treated with luteolin+cisplatin in vivo Cisplatin CTRL Luteolin Luteolin + Cisplatin Luteolin - + - + Cisplatin - - + +

  22. Summary • Luteolin sensitizes cisplatin-induced apoptosis in human cancer cells • The synergistic effect of luteolin+cisplatin is p53-dependent • Luteolin stabilizes p53 protein level via inhibition of protein ubiquitination • Luteolin-mediated JNK activation is responsible for enhanced p53 protein phosphorylation • Luteolin enhances the chemotherapeutic effect of cisplatin in vivo (nude mice xenograft model)

  23. So, luteolin appears to be a potent chemosensitizer in cancer therapy: Luteolin enhances TNF-induced apoptosis in cancer cells Luteolin sensitizes TRAIL-induced apoptosis in cancer cells Luteolin enhances cisplatin-induced cell death both in vitro and in vivo

  24. Acknowledgement Shi Ranxin Zhang Siyuan Ong Yeong Bing Won Yen Kim Zhao Min Huang Qing Ong Her Yam Zhou Jing Ong Choon-Nam Zheng-gang LIU (NIH) Chuanshu HUANG (NYU) Xianglin SHI (NIOSH) Anning LIN (Univ Chicago) Biomedical Research Council Singapore (BMRC) National Medical Research Council Singapore (NMRC) University Academic Research Found (ARF)

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