[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-378028-105":59,"doc-detail-378028-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","bcl-2-family-inhibitors-sensitize-human-cancer-models-to-therapy","Bcl-2 family inhibitors sensitize human cancer models to therapy","","BH3 mimetics that target Bcl-2 family anti-apoptotic proteins offer a therapeutic route in cancers. ABT-199, the first selective Bcl-2 inhibitor, is FDA-approved for hematological malignancies. Using the novel pan-BH3 mimetic IS21, efficacy was tested alone or combined with standard antineoplastic drugs in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 activity correlated with BAX/BAK availability and reduced Bcl-2/Bcl-xL complexes, while sensitization enhanced apoptosis with PARP or MAPK inhibitors, supporting a strategy to boost anticancer treatment.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/bcl-2-family-inhibitors-sensitize-human-cancer-models-to-therapy/378028/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/bcl-2-family-inhibitors-sensitize-human-cancer-models-to-therapy/378028.png","ImageObject",300,407,{"name":92,"@type":93},"Sophia Brooks","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main therapeutic strategy tested in this study?","Question",{"text":112,"@type":113},"The study evaluates whether BH3 mimetics that inhibit Bcl-2 family anti-apoptotic proteins can sensitize cancer models to existing therapies by promoting apoptosis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was IS21 evaluated experimentally?",{"text":117,"@type":113},"IS21 and other BH3 mimetics were tested as single agents and in combination with currently used antineoplastic drugs in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma models.",{"name":119,"@type":110,"acceptedAnswer":120},"What molecular factors predict or enable IS21 sensitivity?",{"text":121,"@type":113},"Protein levels such as Bcl-xL and Mcl-1 predict IS21 sensitivity in melanoma and ovarian cancer, respectively, and IS21 activity depends on the presence of BAX and BAK proteins.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},378028,1790247163,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962084925636,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","[www.nature.com/cddis](www.nature.com/cddis)  \nARTICLE OPEN   \nBcl-2 family inhibitors sensitize human cancer models to therapy  \nElisabetta Valentini 1,11, Marta Di Martile 1,11 ✉, Matteo Brignone1, Marica Di Caprio1, Isabella Manni2, Michela Chiappa3, Ilaria Sergio4, Martina Chiacchiarini 1, Chiara Bazzichetto 1, Fabiana Conciatori1, Simona D’Aguanno 1, Carmen D’Angelo5, Rino Ragno6, Michelangelo Russillo7, Gianni Colotti8, Francesco Marchesi 9, Maria Laura Bellone 10, Fabrizio Dal Piaz 10, Maria Pia Felli4, Giovanna Damia3 and Donatella Del Bufalo 1  \n© The Author(s) 2023  \n|  |  |  |\n| --- | --- | --- |\n|  | BH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT- 199, the first specific Bcl-2 inhibitor, was approved by FDA for the treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| therapeutic strategy to enhance the efficacy of anticancer treatment. |  |  |\n|  | Cell Death and Disease (2023)14:441; [https://doi.org/10.1038/s41419-023-05963-1](https://doi.org/10.1038/s41419-023-05963-1) |  |\n|  |  |  |\n\nINTRODUCTION  \nCancer patients often show intrinsic/innate or acquired resistance to treatments that ultimately result in death [1, 2]; thus, managing these patients represents a challenge, and new therapeutic options are needed. One attractive strategy is the combination of currently available therapies with inhibitors of anti-apoptotic proteins from the Bcl-2 family, which are often expressed at high levels in various types of cancers [3, 4] . Through the interaction with pro-apoptotic proteins, anti-apoptotic proteins allow cells to evade apoptosis, a mechanism frequently defective in cancer affecting the response to therapy [5] . Thus, favoring apoptosis could represent a valuable approach to overcoming resistance.  \nIn 2016, venetoclax/ABT-199, a specific Bcl-2 inhibitor, was approved by the FDA for the treatment of several kinds of leukemia and lymphoma, thus validating the relevance of targeting apoptotic machinery in onco-hematological neoplasms [6] . In addition, the first clinical study analyzing the efficacy of venetoclax in solid tumors evidenced a good activity in metastatic breast cancer [7] . Preclinical results led to the use of combinatorial  \nregimes, including venetoclax or other inhibitors of the Bcl-2 family, in clinical trials under evaluation in cancers of different origins [8, 9] .  \nExperimental findings support the use of anti-apoptotic protein inhibitors in combination therapy both in melanoma and ovarian carcinoma. Inhibition of BRAF and/or MEK/ERK pathways, which together with immunotherapy represent the standard-of-care for melanoma treatment, has been reported to m","cbCaicrnYtKVzJuO","https://ap.wps.com/l/cbCaicrnYtKVzJuO","pdf",5531037,13,"English","# Introduction\n## Rationale for combining therapies with Bcl-2 family anti-apoptotic inhibitors\n## Background on venetoclax and rationale in solid tumor settings\n## Evidence from melanoma and ovarian carcinoma models","[{\"question\":\"What is the main therapeutic strategy tested in this study?\",\"answer\":\"The study evaluates whether BH3 mimetics that inhibit Bcl-2 family anti-apoptotic proteins can sensitize cancer models to existing therapies by promoting apoptosis.\"},{\"question\":\"How was IS21 evaluated experimentally?\",\"answer\":\"IS21 and other BH3 mimetics were tested as single agents and in combination with currently used antineoplastic drugs in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma models.\"},{\"question\":\"What molecular factors predict or enable IS21 sensitivity?\",\"answer\":\"Protein levels such as Bcl-xL and Mcl-1 predict IS21 sensitivity in melanoma and ovarian cancer, respectively, and IS21 activity depends on the presence of BAX and BAK proteins.\"}]","Bcl-2 family inhibitors sensitize human cancer models to therapy | PDF",1790228085,33]