The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis
Background Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor...
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| Veröffentlicht in: | Journal of oral pathology & medicine 2019-05, Vol.48 (5), p.389-399 |
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| creator | De La Chapa, Jorge J. Singha, Prajjal K. Self, Kristen K. Sallaway, McKay L. McHardy, Stanton F. Hart, Matthew J. McGuff, Howard Stan Valdez, Matthew C. Ruiz, Francisco Polusani, Srikanth R. Gonzales, Cara B. |
| description | Background
Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, CIDD‐99, and CIDD‐111).
Methods
Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays.
Results
CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (P |
| doi_str_mv | 10.1111/jop.12843 |
| format | Article |
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Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, CIDD‐99, and CIDD‐111).
Methods
Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays.
Results
CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (P < 0.001). CIDD‐24 was equipotent to the parent compound CPZ, but less potent than CIDD‐99. CIDD‐111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD‐99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti‐cancer effects. All analogs induced an S‐phase block, dose‐dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD‐99 had the most dramatic anti‐tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD‐99 was non‐noxious and demonstrated no observable adverse reactions
Conclusion
This study describes a novel, highly efficacious, CPZ analog, CIDD‐99, with dramatic anti‐tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.</description><identifier>ISSN: 0904-2512</identifier><identifier>EISSN: 1600-0714</identifier><identifier>DOI: 10.1111/jop.12843</identifier><identifier>PMID: 30825343</identifier><language>eng</language><publisher>Denmark: Wiley Subscription Services, Inc</publisher><subject>Animals ; Apoptosis ; Calcium imaging ; Capsaicin - analogs & derivatives ; Capsaicin - pharmacology ; Capsaicin receptors ; Capsazepine ; capsazepine analog ; Carcinoma, Squamous Cell - drug therapy ; Cell cycle ; Cell Line, Tumor ; Cell proliferation ; Depolarization ; Endoplasmic Reticulum Stress ; Female ; Humans ; Isoquinolines - pharmacology ; Male ; Mice ; Mice, Nude ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - pathology ; Mouth Neoplasms - drug therapy ; Oral cancer ; Oral squamous cell carcinoma ; Pain ; Rats ; Rats, Sprague-Dawley ; Squamous cell carcinoma ; Transient receptor potential proteins ; TRPV Cation Channels - antagonists & inhibitors ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Journal of oral pathology & medicine, 2019-05, Vol.48 (5), p.389-399</ispartof><rights>2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><rights>Copyright © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-1739-4574</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjop.12843$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjop.12843$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1416,27923,27924,45573,45574</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30825343$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De La Chapa, Jorge J.</creatorcontrib><creatorcontrib>Singha, Prajjal K.</creatorcontrib><creatorcontrib>Self, Kristen K.</creatorcontrib><creatorcontrib>Sallaway, McKay L.</creatorcontrib><creatorcontrib>McHardy, Stanton F.</creatorcontrib><creatorcontrib>Hart, Matthew J.</creatorcontrib><creatorcontrib>McGuff, Howard Stan</creatorcontrib><creatorcontrib>Valdez, Matthew C.</creatorcontrib><creatorcontrib>Ruiz, Francisco</creatorcontrib><creatorcontrib>Polusani, Srikanth R.</creatorcontrib><creatorcontrib>Gonzales, Cara B.</creatorcontrib><title>The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis</title><title>Journal of oral pathology & medicine</title><addtitle>J Oral Pathol Med</addtitle><description>Background
Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, CIDD‐99, and CIDD‐111).
Methods
Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays.
Results
CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (P < 0.001). CIDD‐24 was equipotent to the parent compound CPZ, but less potent than CIDD‐99. CIDD‐111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD‐99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti‐cancer effects. All analogs induced an S‐phase block, dose‐dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD‐99 had the most dramatic anti‐tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD‐99 was non‐noxious and demonstrated no observable adverse reactions
Conclusion
This study describes a novel, highly efficacious, CPZ analog, CIDD‐99, with dramatic anti‐tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Calcium imaging</subject><subject>Capsaicin - analogs & derivatives</subject><subject>Capsaicin - pharmacology</subject><subject>Capsaicin receptors</subject><subject>Capsazepine</subject><subject>capsazepine analog</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Depolarization</subject><subject>Endoplasmic Reticulum Stress</subject><subject>Female</subject><subject>Humans</subject><subject>Isoquinolines - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - pathology</subject><subject>Mouth Neoplasms - drug therapy</subject><subject>Oral cancer</subject><subject>Oral squamous cell carcinoma</subject><subject>Pain</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Squamous cell carcinoma</subject><subject>Transient receptor potential proteins</subject><subject>TRPV Cation Channels - antagonists & inhibitors</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0904-2512</issn><issn>1600-0714</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkstu1DAUhi1ERYfCghdAlthOWl_iXDZIaFqgqFKramBrObYz8Six3dgZNKz6CH0n3oQnwTO9qPXCtnQ-fb8vB4APGB3jNE7Wzh9jUuX0FZjhAqEMlTh_DWaoRnlGGCaH4G0Ia4RwSXP8BhxSVBFGczoDf5edhtZtdA-l8EH80d5YDYUVvVvN4eL89PTf7V1dz2EwK2taI4WN_RYa25nGxADdKHoYbiYxuClAqfudaJTGukEkCm7MxsHYjW5adVDA5fXVL5yMxirtdZpsTJSaZDTOQtfCs2sY4qhDmMPBRCc7Z9VoUobahnaye26ezqeg8M5HF0x4Bw5a0Qf9_mE9Aj-_ni0X37OLy2_niy8Xmae0oJkqCVWlLBtWVIhpQSlDRKGCEpYz0mglddsQ1FJSsBbldS0pJRgRWqlKClrRI_D53uunZtjhNqbLcz-aQYxb7oThLyvWdHzlNrxgKaXESfDpQTC6m0mHyNduGtNTB04IwTgvMSsS9fF5zJP_8dMScHIP_Da93j7VMeK7bkhOz_fdwH9cXu039D8z1ay9</recordid><startdate>201905</startdate><enddate>201905</enddate><creator>De La Chapa, Jorge J.</creator><creator>Singha, Prajjal K.</creator><creator>Self, Kristen K.</creator><creator>Sallaway, McKay L.</creator><creator>McHardy, Stanton F.</creator><creator>Hart, Matthew J.</creator><creator>McGuff, Howard Stan</creator><creator>Valdez, Matthew C.</creator><creator>Ruiz, Francisco</creator><creator>Polusani, Srikanth R.</creator><creator>Gonzales, Cara B.</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>7QP</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1739-4574</orcidid></search><sort><creationdate>201905</creationdate><title>The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis</title><author>De La Chapa, Jorge J. ; Singha, Prajjal K. ; Self, Kristen K. ; Sallaway, McKay L. ; McHardy, Stanton F. ; Hart, Matthew J. ; McGuff, Howard Stan ; Valdez, Matthew C. ; Ruiz, Francisco ; Polusani, Srikanth R. ; Gonzales, Cara B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p3363-d723d7c7b56805ea33502d06325452bedcefb20f3265f0499c33210238d8ca383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Calcium imaging</topic><topic>Capsaicin - analogs & derivatives</topic><topic>Capsaicin - pharmacology</topic><topic>Capsaicin receptors</topic><topic>Capsazepine</topic><topic>capsazepine analog</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Depolarization</topic><topic>Endoplasmic Reticulum Stress</topic><topic>Female</topic><topic>Humans</topic><topic>Isoquinolines - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mitochondria</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - pathology</topic><topic>Mouth Neoplasms - drug therapy</topic><topic>Oral cancer</topic><topic>Oral squamous cell carcinoma</topic><topic>Pain</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Squamous cell carcinoma</topic><topic>Transient receptor potential proteins</topic><topic>TRPV Cation Channels - antagonists & inhibitors</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De La Chapa, Jorge J.</creatorcontrib><creatorcontrib>Singha, Prajjal K.</creatorcontrib><creatorcontrib>Self, Kristen K.</creatorcontrib><creatorcontrib>Sallaway, McKay L.</creatorcontrib><creatorcontrib>McHardy, Stanton F.</creatorcontrib><creatorcontrib>Hart, Matthew J.</creatorcontrib><creatorcontrib>McGuff, Howard Stan</creatorcontrib><creatorcontrib>Valdez, Matthew C.</creatorcontrib><creatorcontrib>Ruiz, Francisco</creatorcontrib><creatorcontrib>Polusani, Srikanth R.</creatorcontrib><creatorcontrib>Gonzales, Cara B.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of oral pathology & medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De La Chapa, Jorge J.</au><au>Singha, Prajjal K.</au><au>Self, Kristen K.</au><au>Sallaway, McKay L.</au><au>McHardy, Stanton F.</au><au>Hart, Matthew J.</au><au>McGuff, Howard Stan</au><au>Valdez, Matthew C.</au><au>Ruiz, Francisco</au><au>Polusani, Srikanth R.</au><au>Gonzales, Cara B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis</atitle><jtitle>Journal of oral pathology & medicine</jtitle><addtitle>J Oral Pathol Med</addtitle><date>2019-05</date><risdate>2019</risdate><volume>48</volume><issue>5</issue><spage>389</spage><epage>399</epage><pages>389-399</pages><issn>0904-2512</issn><eissn>1600-0714</eissn><abstract>Background
Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, CIDD‐99, and CIDD‐111).
Methods
Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays.
Results
CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (P < 0.001). CIDD‐24 was equipotent to the parent compound CPZ, but less potent than CIDD‐99. CIDD‐111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD‐99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti‐cancer effects. All analogs induced an S‐phase block, dose‐dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD‐99 had the most dramatic anti‐tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD‐99 was non‐noxious and demonstrated no observable adverse reactions
Conclusion
This study describes a novel, highly efficacious, CPZ analog, CIDD‐99, with dramatic anti‐tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.</abstract><cop>Denmark</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30825343</pmid><doi>10.1111/jop.12843</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-1739-4574</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Calcium imaging Capsaicin - analogs & derivatives Capsaicin - pharmacology Capsaicin receptors Capsazepine capsazepine analog Carcinoma, Squamous Cell - drug therapy Cell cycle Cell Line, Tumor Cell proliferation Depolarization Endoplasmic Reticulum Stress Female Humans Isoquinolines - pharmacology Male Mice Mice, Nude Mitochondria Mitochondria - drug effects Mitochondria - pathology Mouth Neoplasms - drug therapy Oral cancer Oral squamous cell carcinoma Pain Rats Rats, Sprague-Dawley Squamous cell carcinoma Transient receptor potential proteins TRPV Cation Channels - antagonists & inhibitors Tumors Xenograft Model Antitumor Assays Xenografts |
| title | The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis |
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