Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs
Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models an...
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| Veröffentlicht in: | Biochemical pharmacology 2012-04, Vol.83 (8), p.995-1004 |
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| container_title | Biochemical pharmacology |
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| creator | Lu, Xiangyi Xiao, Li Wang, Luan Ruden, Douglas M. |
| description | Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans. |
| doi_str_mv | 10.1016/j.bcp.2011.11.011 |
| format | Article |
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Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans.</description><identifier>ISSN: 0006-2952</identifier><identifier>EISSN: 1873-2968</identifier><identifier>DOI: 10.1016/j.bcp.2011.11.011</identifier><identifier>PMID: 22120678</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Antibodies, Monoclonal, Humanized - pharmacology ; anticarcinogenic activity ; antineoplastic agents ; Antineoplastic Agents - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Benzoquinones - therapeutic use ; breast neoplasms ; Breast Neoplasms - drug therapy ; Breast Neoplasms - pathology ; Cancer ; cell cycle ; Cisplatin - pharmacology ; Cisplatin - therapeutic use ; Combined Modality Therapy ; Cysteine Proteinase Inhibitors - pharmacology ; Drug resistance ; Drug Resistance, Neoplasm ; Female ; Geldanamycin ; genetic variation ; Histone Deacetylase Inhibitors - pharmacology ; Hsp90 ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; Humans ; Lactams, Macrocyclic - therapeutic use ; metastasis ; mice ; Neoplasms - drug therapy ; patients ; Proteasome Inhibitors ; proteins ; Taxoids - pharmacology ; therapeutics ; TNF-Related Apoptosis-Inducing Ligand - metabolism ; Trastuzumab ; yeasts</subject><ispartof>Biochemical pharmacology, 2012-04, Vol.83 (8), p.995-1004</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 2011 Elsevier Inc. All rights reserved.</rights><rights>2011 Elsevier Inc. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-3033ee0833366195a0809017f3b89fbc64bc11c6e15ac118fe49d11624971e143</citedby><cites>FETCH-LOGICAL-c540t-3033ee0833366195a0809017f3b89fbc64bc11c6e15ac118fe49d11624971e143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bcp.2011.11.011$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22120678$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Xiangyi</creatorcontrib><creatorcontrib>Xiao, Li</creatorcontrib><creatorcontrib>Wang, Luan</creatorcontrib><creatorcontrib>Ruden, Douglas M.</creatorcontrib><title>Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs</title><title>Biochemical pharmacology</title><addtitle>Biochem Pharmacol</addtitle><description>Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans.</description><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>anticarcinogenic activity</subject><subject>antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Benzoquinones - therapeutic use</subject><subject>breast neoplasms</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>cell cycle</subject><subject>Cisplatin - pharmacology</subject><subject>Cisplatin - therapeutic use</subject><subject>Combined Modality Therapy</subject><subject>Cysteine Proteinase Inhibitors - pharmacology</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Female</subject><subject>Geldanamycin</subject><subject>genetic variation</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Hsp90</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>Humans</subject><subject>Lactams, Macrocyclic - therapeutic use</subject><subject>metastasis</subject><subject>mice</subject><subject>Neoplasms - drug therapy</subject><subject>patients</subject><subject>Proteasome Inhibitors</subject><subject>proteins</subject><subject>Taxoids - pharmacology</subject><subject>therapeutics</subject><subject>TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>Trastuzumab</subject><subject>yeasts</subject><issn>0006-2952</issn><issn>1873-2968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UdGK1TAQDaK419UP8EXzA71mkjZNFQRZ1BUWfHD3OaTp9N653NuUJLvgV_jLpltdFEQYmBPmzJnJHMZegtiCAP3msO39vJUCYFuipEdsA6ZVley0ecw2QghdcCPP2LOUDsvTaHjKzqQEKXRrNuzHZZo7wWnaU085xMTdNPAh3u54xEQpu8ljKXO_gPiWX--RzyHjlMkdeY8TjpQTDyP34dTT5DKFiec9RjcT3hf-OSIslIIyVav0_dD0nD0Z3THhi1_5nN18-nh9cVldff385eLDVeWbWuRKCaUQhVFKaQ1d44QRnYB2VL3pxt7ruvcAXiM0rgAzYt0NAFrWXQsItTpn71fd-bY_4eDLf6I72jnSycXvNjiyf1cm2ttduLNKdp1pTRGAVcDHkFLE8aEXhF3csQdb3LGLO7ZESaXn1Z9DHzp-21EIr1fC6IJ1u0jJ3nwrCk2xTsrGLHu_WxlYjnNHGG3yhOV-A0X02Q6B_rPAT2hnq3I</recordid><startdate>20120415</startdate><enddate>20120415</enddate><creator>Lu, Xiangyi</creator><creator>Xiao, Li</creator><creator>Wang, Luan</creator><creator>Ruden, Douglas M.</creator><general>Elsevier Inc</general><scope>FBQ</scope><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>5PM</scope></search><sort><creationdate>20120415</creationdate><title>Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs</title><author>Lu, Xiangyi ; Xiao, Li ; Wang, Luan ; Ruden, Douglas M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-3033ee0833366195a0809017f3b89fbc64bc11c6e15ac118fe49d11624971e143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>anticarcinogenic activity</topic><topic>antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Benzoquinones - therapeutic use</topic><topic>breast neoplasms</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>cell cycle</topic><topic>Cisplatin - pharmacology</topic><topic>Cisplatin - therapeutic use</topic><topic>Combined Modality Therapy</topic><topic>Cysteine Proteinase Inhibitors - pharmacology</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Female</topic><topic>Geldanamycin</topic><topic>genetic variation</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Hsp90</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>Humans</topic><topic>Lactams, Macrocyclic - therapeutic use</topic><topic>metastasis</topic><topic>mice</topic><topic>Neoplasms - drug therapy</topic><topic>patients</topic><topic>Proteasome Inhibitors</topic><topic>proteins</topic><topic>Taxoids - pharmacology</topic><topic>therapeutics</topic><topic>TNF-Related Apoptosis-Inducing Ligand - metabolism</topic><topic>Trastuzumab</topic><topic>yeasts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Xiangyi</creatorcontrib><creatorcontrib>Xiao, Li</creatorcontrib><creatorcontrib>Wang, Luan</creatorcontrib><creatorcontrib>Ruden, Douglas M.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biochemical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Xiangyi</au><au>Xiao, Li</au><au>Wang, Luan</au><au>Ruden, Douglas M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs</atitle><jtitle>Biochemical pharmacology</jtitle><addtitle>Biochem Pharmacol</addtitle><date>2012-04-15</date><risdate>2012</risdate><volume>83</volume><issue>8</issue><spage>995</spage><epage>1004</epage><pages>995-1004</pages><issn>0006-2952</issn><eissn>1873-2968</eissn><abstract>Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>22120678</pmid><doi>10.1016/j.bcp.2011.11.011</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Antibodies, Monoclonal, Humanized - pharmacology anticarcinogenic activity antineoplastic agents Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Benzoquinones - therapeutic use breast neoplasms Breast Neoplasms - drug therapy Breast Neoplasms - pathology Cancer cell cycle Cisplatin - pharmacology Cisplatin - therapeutic use Combined Modality Therapy Cysteine Proteinase Inhibitors - pharmacology Drug resistance Drug Resistance, Neoplasm Female Geldanamycin genetic variation Histone Deacetylase Inhibitors - pharmacology Hsp90 HSP90 Heat-Shock Proteins - antagonists & inhibitors Humans Lactams, Macrocyclic - therapeutic use metastasis mice Neoplasms - drug therapy patients Proteasome Inhibitors proteins Taxoids - pharmacology therapeutics TNF-Related Apoptosis-Inducing Ligand - metabolism Trastuzumab yeasts |
| title | Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs |
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