Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells
Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long‐term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases su...
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| Veröffentlicht in: | Chembiochem : a European journal of chemical biology 2021-12, Vol.22 (24), p.3391-3397 |
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| container_title | Chembiochem : a European journal of chemical biology |
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| creator | Jana, Batakrishna Kim, Sangpil Chae, Jae‐Byoung Chung, Hyewon Kim, Chaekyu Ryu, Ja‐Hyoung |
| description | Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long‐term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria‐targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl‐monoquaternary ammonium‐triphenyl phosphine (TPP) and alkyl‐diquaternary ammonium‐TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl‐diquaternary ammonium‐TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.
Many characteristics of senescence are associated with mitochondria. Here, we showcase the importance of hydrophobicity and charge during the design of new mitochondria‐targeted small molecules as a senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging. |
| doi_str_mv | 10.1002/cbic.202100412 |
| format | Article |
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Many characteristics of senescence are associated with mitochondria. Here, we showcase the importance of hydrophobicity and charge during the design of new mitochondria‐targeted small molecules as a senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.</description><identifier>ISSN: 1439-4227</identifier><identifier>EISSN: 1439-7633</identifier><identifier>DOI: 10.1002/cbic.202100412</identifier><identifier>PMID: 34580971</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Aging ; alkyl-quaternary ammonium-TPP ; Ammonium ; Ammonium Compounds - chemistry ; Ammonium Compounds - pharmacology ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Arteriosclerosis ; Atherosclerosis ; Benzene Derivatives - chemistry ; Benzene Derivatives - pharmacology ; Bioaccumulation ; Cell cycle ; Cell Survival - drug effects ; Cellular Senescence - drug effects ; Chains ; Diabetes mellitus ; Disruption ; Drug Screening Assays, Antitumor ; HEK293 Cells ; Humans ; membrane disruption ; Membranes ; Mice ; Mitochondria ; Mitochondrial Membranes - drug effects ; Molecular Structure ; NIH 3T3 Cells ; Phosphine ; Phosphines ; Phosphines - chemistry ; Phosphines - pharmacology ; Reactive oxygen species ; Senescence ; Senescentretina mouse model ; Tumorigenesis</subject><ispartof>Chembiochem : a European journal of chemical biology, 2021-12, Vol.22 (24), p.3391-3397</ispartof><rights>2021 Wiley‐VCH GmbH</rights><rights>2021 Wiley-VCH GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3732-e8b56c7192759b323e56b724d3551e2be93a0f832e925c7c1b79193c63758fe93</citedby><cites>FETCH-LOGICAL-c3732-e8b56c7192759b323e56b724d3551e2be93a0f832e925c7c1b79193c63758fe93</cites><orcidid>0000-0003-2944-0109 ; 0000-0003-0252-0985</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcbic.202100412$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcbic.202100412$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34580971$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jana, Batakrishna</creatorcontrib><creatorcontrib>Kim, Sangpil</creatorcontrib><creatorcontrib>Chae, Jae‐Byoung</creatorcontrib><creatorcontrib>Chung, Hyewon</creatorcontrib><creatorcontrib>Kim, Chaekyu</creatorcontrib><creatorcontrib>Ryu, Ja‐Hyoung</creatorcontrib><title>Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells</title><title>Chembiochem : a European journal of chemical biology</title><addtitle>Chembiochem</addtitle><description>Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long‐term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria‐targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl‐monoquaternary ammonium‐triphenyl phosphine (TPP) and alkyl‐diquaternary ammonium‐TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl‐diquaternary ammonium‐TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.
Many characteristics of senescence are associated with mitochondria. Here, we showcase the importance of hydrophobicity and charge during the design of new mitochondria‐targeted small molecules as a senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.</description><subject>Aging</subject><subject>alkyl-quaternary ammonium-TPP</subject><subject>Ammonium</subject><subject>Ammonium Compounds - chemistry</subject><subject>Ammonium Compounds - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Arteriosclerosis</subject><subject>Atherosclerosis</subject><subject>Benzene Derivatives - chemistry</subject><subject>Benzene Derivatives - pharmacology</subject><subject>Bioaccumulation</subject><subject>Cell cycle</subject><subject>Cell Survival - drug effects</subject><subject>Cellular Senescence - drug effects</subject><subject>Chains</subject><subject>Diabetes mellitus</subject><subject>Disruption</subject><subject>Drug Screening Assays, Antitumor</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>membrane disruption</subject><subject>Membranes</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Mitochondrial Membranes - drug effects</subject><subject>Molecular Structure</subject><subject>NIH 3T3 Cells</subject><subject>Phosphine</subject><subject>Phosphines</subject><subject>Phosphines - chemistry</subject><subject>Phosphines - pharmacology</subject><subject>Reactive oxygen species</subject><subject>Senescence</subject><subject>Senescentretina mouse model</subject><subject>Tumorigenesis</subject><issn>1439-4227</issn><issn>1439-7633</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkD1PwzAQhi0EolBYGVEkFpYWf8RxPEL4qmjFQJmtxL2AKzcudgLqv8dVS5FYmOy7e_zq_CB0RvCQYEyvdGX0kGIai5TQPXREUiYHImNsf3tPKRU9dBzCHGMsM0YOUY-lPMdSkCM0nZjW6XfXzLwpbTKBReXLBpJbE3y3bE3zlkycBd1ZCEntfPICsWrNJyRPxtr13NWx2UDQ0LRJAdaGE3RQlzbA6fbso9f7u2nxOBg_P4yK6_FAM8HoAPKKZ1oQSQWXFaMMeFYJms4Y5wRoBZKVuM4ZBUm5FppUQhLJdMYEz-s47aPLTe7Su48OQqsWJq5hbfyB64KiXIiUp5LjiF78Qeeu803cTtEM5ymReZTWR8MNpb0LwUOtlt4sSr9SBKu1b7X2rXa-44PzbWxXLWC2w38ER0BugC9jYfVPnCpuRsVv-DdTwIqJ</recordid><startdate>20211210</startdate><enddate>20211210</enddate><creator>Jana, Batakrishna</creator><creator>Kim, Sangpil</creator><creator>Chae, Jae‐Byoung</creator><creator>Chung, Hyewon</creator><creator>Kim, Chaekyu</creator><creator>Ryu, Ja‐Hyoung</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2944-0109</orcidid><orcidid>https://orcid.org/0000-0003-0252-0985</orcidid></search><sort><creationdate>20211210</creationdate><title>Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells</title><author>Jana, Batakrishna ; Kim, Sangpil ; Chae, Jae‐Byoung ; Chung, Hyewon ; Kim, Chaekyu ; Ryu, Ja‐Hyoung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3732-e8b56c7192759b323e56b724d3551e2be93a0f832e925c7c1b79193c63758fe93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aging</topic><topic>alkyl-quaternary ammonium-TPP</topic><topic>Ammonium</topic><topic>Ammonium Compounds - chemistry</topic><topic>Ammonium Compounds - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Arteriosclerosis</topic><topic>Atherosclerosis</topic><topic>Benzene Derivatives - chemistry</topic><topic>Benzene Derivatives - pharmacology</topic><topic>Bioaccumulation</topic><topic>Cell cycle</topic><topic>Cell Survival - drug effects</topic><topic>Cellular Senescence - drug effects</topic><topic>Chains</topic><topic>Diabetes mellitus</topic><topic>Disruption</topic><topic>Drug Screening Assays, Antitumor</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>membrane disruption</topic><topic>Membranes</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>Mitochondrial Membranes - drug effects</topic><topic>Molecular Structure</topic><topic>NIH 3T3 Cells</topic><topic>Phosphine</topic><topic>Phosphines</topic><topic>Phosphines - chemistry</topic><topic>Phosphines - pharmacology</topic><topic>Reactive oxygen species</topic><topic>Senescence</topic><topic>Senescentretina mouse model</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jana, Batakrishna</creatorcontrib><creatorcontrib>Kim, Sangpil</creatorcontrib><creatorcontrib>Chae, Jae‐Byoung</creatorcontrib><creatorcontrib>Chung, Hyewon</creatorcontrib><creatorcontrib>Kim, Chaekyu</creatorcontrib><creatorcontrib>Ryu, Ja‐Hyoung</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chembiochem : a European journal of chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jana, Batakrishna</au><au>Kim, Sangpil</au><au>Chae, Jae‐Byoung</au><au>Chung, Hyewon</au><au>Kim, Chaekyu</au><au>Ryu, Ja‐Hyoung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells</atitle><jtitle>Chembiochem : a European journal of chemical biology</jtitle><addtitle>Chembiochem</addtitle><date>2021-12-10</date><risdate>2021</risdate><volume>22</volume><issue>24</issue><spage>3391</spage><epage>3397</epage><pages>3391-3397</pages><issn>1439-4227</issn><eissn>1439-7633</eissn><abstract>Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long‐term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria‐targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl‐monoquaternary ammonium‐triphenyl phosphine (TPP) and alkyl‐diquaternary ammonium‐TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl‐diquaternary ammonium‐TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.
Many characteristics of senescence are associated with mitochondria. Here, we showcase the importance of hydrophobicity and charge during the design of new mitochondria‐targeted small molecules as a senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34580971</pmid><doi>10.1002/cbic.202100412</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-2944-0109</orcidid><orcidid>https://orcid.org/0000-0003-0252-0985</orcidid></addata></record> |
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| ispartof | Chembiochem : a European journal of chemical biology, 2021-12, Vol.22 (24), p.3391-3397 |
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| subjects | Aging alkyl-quaternary ammonium-TPP Ammonium Ammonium Compounds - chemistry Ammonium Compounds - pharmacology Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Arteriosclerosis Atherosclerosis Benzene Derivatives - chemistry Benzene Derivatives - pharmacology Bioaccumulation Cell cycle Cell Survival - drug effects Cellular Senescence - drug effects Chains Diabetes mellitus Disruption Drug Screening Assays, Antitumor HEK293 Cells Humans membrane disruption Membranes Mice Mitochondria Mitochondrial Membranes - drug effects Molecular Structure NIH 3T3 Cells Phosphine Phosphines Phosphines - chemistry Phosphines - pharmacology Reactive oxygen species Senescence Senescentretina mouse model Tumorigenesis |
| title | Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells |
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