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induction of apoptosis by marine alkaloid analogs in human cervical cancer cells

Forming digits. Forming lumen. Losing tail. Mullerian or wolffian. Adjusting cell number. Eliminating infected cells. Eliminating injured cells. Different roles forApoptosis. Apoptosis: Target for novel drugs. Targeting apoptotic cell death pathways provides wide-ranging opportunities for the discovery and development of novel drugsMost traditional cancer chemotherapy drugs exert their cytotoxic effects by inducing apoptosis Numerous pro-apoptotic drugs for treating cancer are currently be224

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induction of apoptosis by marine alkaloid analogs in human cervical cancer cells

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    1. Induction of apoptosis by marine alkaloid analogs in human cervical cancer cells D. Karunagaran Department of Biotechnology Indian Institute of Technology Madras MKU Jan 4, 2010

    4. Apoptosis: Target for novel drugs Targeting apoptotic cell death pathways provides wide-ranging opportunities for the discovery and development of novel drugs Most traditional cancer chemotherapy drugs exert their cytotoxic effects by inducing apoptosis Numerous pro-apoptotic drugs for treating cancer are currently being developed. Scrip magazine: “the two most popular strategies in the whole of R&D are angiogenesis inhibition and apoptosis induction”

    5. Marine alkaloids For the past quarter of a century, global marine sources have proven to be a rich source of new medicinally valuable compounds These natural products exist as secondary metabolites in marine invertebrates such as sponges, bryazoa, tunicates and ascidians About a dozen of marine alkaloids are currently in various phases of human clinical trials for treatment of different cancers (Newman DJ et al) Most bioactive compounds from sponges have exhibited a variety of activities such as anti-inflammatory, antitumor, immunosuppressive, neurosuppressive, antiviral, antimalarial and antibiotic activities Many alkaloids with unique structures are available only in minute quantities, precluding their thorough biological evaluations. Laboratory synthesis of these alkaloids is the only practical solution to this problem.

    8. Dr. KNR has isolated kuanoniamine from marine tunicates collected from south Indian coast A molecular modeling study of kuanoniamine led him to cinnamoyl thiazolyl ketones as a set of compounds worthy of synthesis This line of reasoning led us further to connect our interest in marine alkaloids and curcumins, both classes being cytotoxic, to design curcumin-alkaloid hybrids

    11. Cytotoxic activity of KNR3

    12. Acridine orange/EtBr Staining

    13. DAPI Staining

    14. Cell cycle analysis 24h

    16. Caspase 3 assay

    17. Caspase 9 assay

    18. JC-1 Staining

    19. RT-PCR analysis

    21. Cytotoxic effects of KNR7 and KNR8

    22. DAPI Staining

    23. Cell Cycle analysis

    24. NF-kB Luciferase assay

    25. Conclusions KNR3 was very effective in inducing G2-M cell cycle arrest followed by apoptosis at 1µM in HeLa and other cancer cells KNR3 induces apoptosis via activation of caspases 9 and 3, downregulation of XIAP, BClXL indicating the involvement of intrinsic apoptotic pathway KNR7 and KNR8, curcumin-marine alkaloid analog hybrids were also found to possess anti-proliferative and apoptotic activity at higher concentrations KNR8 was found to be more effective than curcumin at 30µM Further experiments need to be done to understand their mechanisms of action

    26. Future plans Caspase fluorometric assays for KNR7 and 8 compounds To investigate the role of mitochondria in inducing apoptosis on drug treatment with KNR7 and 8 To look for the status of NF-?B pathway/wnt signaling in HeLa cells

    28. THANK YOU

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