Advances in Cancer Drug Targets

Volume: 1

Cellular FLICE-Like Inhibitory Protein (c-FLIP): A Key Anti- Apoptotic Factor and a Target for Cancer Therapy

Author(s): Ahmad R. Safa

Pp: 120-145 (26)

DOI: 10.2174/9781608054749113010006

* (Excluding Mailing and Handling)

Abstract

Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of apoptosis. c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, TNF-related apoptosis-inducing ligand (TRAIL), and chemotherapy-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIPL) and short (c-FLIPS) splice variants in human cells. Accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIPL in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, several chemotherapeutic agents induce c-FLIP downregulation in neoplastic cells. Moreover, numerous small molecule inhibitors have been found which cause degradation of c-FLIP variants and decrease mRNA and protein levels of c-FLIPL and c-FLIPS. In this chapter, I assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.


Keywords: Taxol, apoptosis, caspase-8, caspase-10, c-FLIP, leukemia, death receptors.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739835005 and j.to_date >= 1739835005 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4782) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739835005 and j.to_date >= 1739835005 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4782) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739835005 and j.to_date >= 1739835005 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 4782)
      690μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1176 and `b`.`banner_from_date` <= 1739835005 and `b`.`banner_to_date` >= 1739835005 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.13msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1176
      • 3: 1739835005
      • 4: 1739835005
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='430cfb16e4132de1c2460f97a2391a99'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    7Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        A6Wij6Wuz2n7vdAUk1AZeycvCdyEQ0cFzB3tHtE4
        uc_cart_id
        430cfb16e4132de1c2460f97a2391a99
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/4782" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/4782
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
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        request_cookies
        0 of 0
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        response_headers
        0 of 0
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        session_attributes
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        array:5 [ "_token" => "A6Wij6Wuz2n7vdAUk1AZeycvCdyEQ0cFzB3tHtE4" "uc_cart_id" => "430cfb16e4132de1c2460f97a2391a99" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/4782" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:30:05GET/chapter/4782112199