Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells
Purpose Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Recen...
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| Veröffentlicht in: | Cancer chemotherapy and pharmacology 2021-11, Vol.88 (5), p.845-856 |
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| creator | Huot, Marielle Caron, Maxime Richer, Chantal Djibo, Rahinatou Najmanovich, Rafael St-Onge, Pascal Sinnett, Daniel Raynal, Noël J. M. |
| description | Purpose
Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Recently, we have demonstrated that the heart failure drug, proscillaridin A, produced anticancer effects with specificity toward MYC expressing leukemia cells. We also reported that decitabine, a hypomethylating drug, synergizes with proscillaridin A in colon cancer cells. Here, we investigated whether proscillaridin A exhibits epigenetic and anticancer activity against eRMS RD cells, overexpressing MYC oncogene, and its combination with decitabine.
Methods
We investigated the anticancer effects of proscillaridin A in eRMS RD cells in vitro. In response to drug treatment, we measured growth inhibition, cell cycle arrest, loss of clonogenicity and self-renewal capacity. We further evaluated the impact of proscillaridin A on MYC expression and its downstream transcriptomic effects by RNA sequencing. Then, we measured protein expression of epigenetic regulators and their associated chromatin post-translational modifications in response to drug treatment. Chromatin immunoprecipitation sequencing data sets were coupled with transcriptomic results to pinpoint the impact of proscillaridin A on gene pathways associated with specific chromatin modifications. Lastly, we evaluated the effect of the combination of proscillaridin A and the DNA demethylating drug decitabine on eRMS RD cell growth and clonogenic potential.
Results
Clinically relevant concentration of proscillaridin A (5 nM) produced growth inhibition, cell cycle arrest and loss of clonogenicity in eRMS RD cells. Proscillaridin A produced a significant downregulation of MYC protein expression and inhibition of oncogenic transcriptional programs controlled by MYC, involved in cell replication. Interestingly, significant reduction in total histone 3 acetylation and on specific lysine residues (lysine 9, 14, 18, and 27 on histone 3) was associated with significant protein downregulation of a series of lysine acetyltransferases (KAT3A, KAT3B, KAT2A, KAT2B, and KAT5). In addition, proscillaridin A produced synergistic growth inhibition and loss of clonogenicity when combined with the approved DNA demethylating drug decitabine.
Conclusion
Proscillaridin A produces anticancer and epigenetic effects in the low nanomolar ra |
| doi_str_mv | 10.1007/s00280-021-04339-6 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2557232201</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2577919612</sourcerecordid><originalsourceid>FETCH-LOGICAL-c375t-d8779825f2119a1f6de41b4841188dbe6d3ed589854a5535e2a05a4f091d4a003</originalsourceid><addsrcrecordid>eNp9kUtr3DAUhUVpaSZJ_0AXRdBNN27v1cOWlyHpCwKFkKzFtSVPFGxrKtmE-ffVZNIWuuhGAuk75z4OY28RPiJA8ykDCAMVCKxASdlW9Qu2QSVFBUbJl2wDUqlKN6BO2GnODwCgUMrX7EQWHBHMhm1v_G5Nu5jDvOW7FHMfxpFScGHmF7wcfZy6MNMS4swfw3LPne_DQuXNc9pSmPPC_dSlfZxp5OmeOhenfcyUipL4zRXv_Tjmc_ZqoDH7N8_3Gbv78vn28lt1_ePr98uL66qXjV4qZ5qmNUIPArElHGrnFXbKKERjXOdrJ73TpjVakdZSe0GgSQ3QolMEIM_Yh6NvmeXn6vNip5APHdDs45qt0LoRUgjAgr7_B32IaypTHKjSBrY1ikKJI9WX5eTkB7tLYaK0twj2EIM9xmBLDPYpBlsX0btn67WbvPsj-b33AsgjkMvXvPXpb-3_2P4Ci-GSmw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2577919612</pqid></control><display><type>article</type><title>Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Huot, Marielle ; Caron, Maxime ; Richer, Chantal ; Djibo, Rahinatou ; Najmanovich, Rafael ; St-Onge, Pascal ; Sinnett, Daniel ; Raynal, Noël J. M.</creator><creatorcontrib>Huot, Marielle ; Caron, Maxime ; Richer, Chantal ; Djibo, Rahinatou ; Najmanovich, Rafael ; St-Onge, Pascal ; Sinnett, Daniel ; Raynal, Noël J. M.</creatorcontrib><description>Purpose
Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Recently, we have demonstrated that the heart failure drug, proscillaridin A, produced anticancer effects with specificity toward MYC expressing leukemia cells. We also reported that decitabine, a hypomethylating drug, synergizes with proscillaridin A in colon cancer cells. Here, we investigated whether proscillaridin A exhibits epigenetic and anticancer activity against eRMS RD cells, overexpressing MYC oncogene, and its combination with decitabine.
Methods
We investigated the anticancer effects of proscillaridin A in eRMS RD cells in vitro. In response to drug treatment, we measured growth inhibition, cell cycle arrest, loss of clonogenicity and self-renewal capacity. We further evaluated the impact of proscillaridin A on MYC expression and its downstream transcriptomic effects by RNA sequencing. Then, we measured protein expression of epigenetic regulators and their associated chromatin post-translational modifications in response to drug treatment. Chromatin immunoprecipitation sequencing data sets were coupled with transcriptomic results to pinpoint the impact of proscillaridin A on gene pathways associated with specific chromatin modifications. Lastly, we evaluated the effect of the combination of proscillaridin A and the DNA demethylating drug decitabine on eRMS RD cell growth and clonogenic potential.
Results
Clinically relevant concentration of proscillaridin A (5 nM) produced growth inhibition, cell cycle arrest and loss of clonogenicity in eRMS RD cells. Proscillaridin A produced a significant downregulation of MYC protein expression and inhibition of oncogenic transcriptional programs controlled by MYC, involved in cell replication. Interestingly, significant reduction in total histone 3 acetylation and on specific lysine residues (lysine 9, 14, 18, and 27 on histone 3) was associated with significant protein downregulation of a series of lysine acetyltransferases (KAT3A, KAT3B, KAT2A, KAT2B, and KAT5). In addition, proscillaridin A produced synergistic growth inhibition and loss of clonogenicity when combined with the approved DNA demethylating drug decitabine.
Conclusion
Proscillaridin A produces anticancer and epigenetic effects in the low nanomolar range and its combination with decitabine warrants further investigation for the treatment of eRMS.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-021-04339-6</identifier><identifier>PMID: 34331108</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>5-aza-2'-deoxycytidine ; Acetylation ; Acetylation - drug effects ; Anticancer properties ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antitumor activity ; Cancer ; Cancer Research ; Cell cycle ; Cell Line, Tumor ; Cell Self Renewal - drug effects ; Cell self-renewal ; Chromatin ; Colon ; Colon cancer ; Congestive heart failure ; Decitabine - administration & dosage ; Deoxyribonucleic acid ; DNA ; Drug Repositioning ; Epigenetics ; Evaluation ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene sequencing ; Histones ; Histones - metabolism ; Humans ; Immunoprecipitation ; Investigations ; Leukemia ; Lysine ; Lysine - metabolism ; Medicine ; Medicine & Public Health ; Muscles ; Myc protein ; Neoplasm Proteins ; Oncology ; Original Article ; Pharmacology/Toxicology ; Post-translation ; Promoter Regions, Genetic - drug effects ; Proscillaridin - administration & dosage ; Proscillaridin - pharmacology ; Protein expression ; Proteins ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Rhabdomyosarcoma ; Rhabdomyosarcoma, Embryonal - drug therapy ; Rhabdomyosarcoma, Embryonal - genetics ; Rhabdomyosarcoma, Embryonal - pathology ; Skeletal muscle ; Transcription ; Transcriptomics</subject><ispartof>Cancer chemotherapy and pharmacology, 2021-11, Vol.88 (5), p.845-856</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-d8779825f2119a1f6de41b4841188dbe6d3ed589854a5535e2a05a4f091d4a003</citedby><cites>FETCH-LOGICAL-c375t-d8779825f2119a1f6de41b4841188dbe6d3ed589854a5535e2a05a4f091d4a003</cites><orcidid>0000-0002-4241-6800</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00280-021-04339-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00280-021-04339-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34331108$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huot, Marielle</creatorcontrib><creatorcontrib>Caron, Maxime</creatorcontrib><creatorcontrib>Richer, Chantal</creatorcontrib><creatorcontrib>Djibo, Rahinatou</creatorcontrib><creatorcontrib>Najmanovich, Rafael</creatorcontrib><creatorcontrib>St-Onge, Pascal</creatorcontrib><creatorcontrib>Sinnett, Daniel</creatorcontrib><creatorcontrib>Raynal, Noël J. M.</creatorcontrib><title>Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Recently, we have demonstrated that the heart failure drug, proscillaridin A, produced anticancer effects with specificity toward MYC expressing leukemia cells. We also reported that decitabine, a hypomethylating drug, synergizes with proscillaridin A in colon cancer cells. Here, we investigated whether proscillaridin A exhibits epigenetic and anticancer activity against eRMS RD cells, overexpressing MYC oncogene, and its combination with decitabine.
Methods
We investigated the anticancer effects of proscillaridin A in eRMS RD cells in vitro. In response to drug treatment, we measured growth inhibition, cell cycle arrest, loss of clonogenicity and self-renewal capacity. We further evaluated the impact of proscillaridin A on MYC expression and its downstream transcriptomic effects by RNA sequencing. Then, we measured protein expression of epigenetic regulators and their associated chromatin post-translational modifications in response to drug treatment. Chromatin immunoprecipitation sequencing data sets were coupled with transcriptomic results to pinpoint the impact of proscillaridin A on gene pathways associated with specific chromatin modifications. Lastly, we evaluated the effect of the combination of proscillaridin A and the DNA demethylating drug decitabine on eRMS RD cell growth and clonogenic potential.
Results
Clinically relevant concentration of proscillaridin A (5 nM) produced growth inhibition, cell cycle arrest and loss of clonogenicity in eRMS RD cells. Proscillaridin A produced a significant downregulation of MYC protein expression and inhibition of oncogenic transcriptional programs controlled by MYC, involved in cell replication. Interestingly, significant reduction in total histone 3 acetylation and on specific lysine residues (lysine 9, 14, 18, and 27 on histone 3) was associated with significant protein downregulation of a series of lysine acetyltransferases (KAT3A, KAT3B, KAT2A, KAT2B, and KAT5). In addition, proscillaridin A produced synergistic growth inhibition and loss of clonogenicity when combined with the approved DNA demethylating drug decitabine.
Conclusion
Proscillaridin A produces anticancer and epigenetic effects in the low nanomolar range and its combination with decitabine warrants further investigation for the treatment of eRMS.</description><subject>5-aza-2'-deoxycytidine</subject><subject>Acetylation</subject><subject>Acetylation - drug effects</subject><subject>Anticancer properties</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antitumor activity</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Self Renewal - drug effects</subject><subject>Cell self-renewal</subject><subject>Chromatin</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Congestive heart failure</subject><subject>Decitabine - administration & dosage</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drug Repositioning</subject><subject>Epigenetics</subject><subject>Evaluation</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene sequencing</subject><subject>Histones</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Investigations</subject><subject>Leukemia</subject><subject>Lysine</subject><subject>Lysine - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Muscles</subject><subject>Myc protein</subject><subject>Neoplasm Proteins</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacology/Toxicology</subject><subject>Post-translation</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>Proscillaridin - administration & dosage</subject><subject>Proscillaridin - pharmacology</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Rhabdomyosarcoma</subject><subject>Rhabdomyosarcoma, Embryonal - drug therapy</subject><subject>Rhabdomyosarcoma, Embryonal - genetics</subject><subject>Rhabdomyosarcoma, Embryonal - pathology</subject><subject>Skeletal muscle</subject><subject>Transcription</subject><subject>Transcriptomics</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kUtr3DAUhUVpaSZJ_0AXRdBNN27v1cOWlyHpCwKFkKzFtSVPFGxrKtmE-ffVZNIWuuhGAuk75z4OY28RPiJA8ykDCAMVCKxASdlW9Qu2QSVFBUbJl2wDUqlKN6BO2GnODwCgUMrX7EQWHBHMhm1v_G5Nu5jDvOW7FHMfxpFScGHmF7wcfZy6MNMS4swfw3LPne_DQuXNc9pSmPPC_dSlfZxp5OmeOhenfcyUipL4zRXv_Tjmc_ZqoDH7N8_3Gbv78vn28lt1_ePr98uL66qXjV4qZ5qmNUIPArElHGrnFXbKKERjXOdrJ73TpjVakdZSe0GgSQ3QolMEIM_Yh6NvmeXn6vNip5APHdDs45qt0LoRUgjAgr7_B32IaypTHKjSBrY1ikKJI9WX5eTkB7tLYaK0twj2EIM9xmBLDPYpBlsX0btn67WbvPsj-b33AsgjkMvXvPXpb-3_2P4Ci-GSmw</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Huot, Marielle</creator><creator>Caron, Maxime</creator><creator>Richer, Chantal</creator><creator>Djibo, Rahinatou</creator><creator>Najmanovich, Rafael</creator><creator>St-Onge, Pascal</creator><creator>Sinnett, Daniel</creator><creator>Raynal, Noël J. M.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</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>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4241-6800</orcidid></search><sort><creationdate>20211101</creationdate><title>Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells</title><author>Huot, Marielle ; Caron, Maxime ; Richer, Chantal ; Djibo, Rahinatou ; Najmanovich, Rafael ; St-Onge, Pascal ; Sinnett, Daniel ; Raynal, Noël J. M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-d8779825f2119a1f6de41b4841188dbe6d3ed589854a5535e2a05a4f091d4a003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>5-aza-2'-deoxycytidine</topic><topic>Acetylation</topic><topic>Acetylation - drug effects</topic><topic>Anticancer properties</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Antitumor activity</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell Self Renewal - drug effects</topic><topic>Cell self-renewal</topic><topic>Chromatin</topic><topic>Colon</topic><topic>Colon cancer</topic><topic>Congestive heart failure</topic><topic>Decitabine - administration & dosage</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drug Repositioning</topic><topic>Epigenetics</topic><topic>Evaluation</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene sequencing</topic><topic>Histones</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Investigations</topic><topic>Leukemia</topic><topic>Lysine</topic><topic>Lysine - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Muscles</topic><topic>Myc protein</topic><topic>Neoplasm Proteins</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacology/Toxicology</topic><topic>Post-translation</topic><topic>Promoter Regions, Genetic - drug effects</topic><topic>Proscillaridin - administration & dosage</topic><topic>Proscillaridin - pharmacology</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Rhabdomyosarcoma</topic><topic>Rhabdomyosarcoma, Embryonal - drug therapy</topic><topic>Rhabdomyosarcoma, Embryonal - genetics</topic><topic>Rhabdomyosarcoma, Embryonal - pathology</topic><topic>Skeletal muscle</topic><topic>Transcription</topic><topic>Transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huot, Marielle</creatorcontrib><creatorcontrib>Caron, Maxime</creatorcontrib><creatorcontrib>Richer, Chantal</creatorcontrib><creatorcontrib>Djibo, Rahinatou</creatorcontrib><creatorcontrib>Najmanovich, Rafael</creatorcontrib><creatorcontrib>St-Onge, Pascal</creatorcontrib><creatorcontrib>Sinnett, Daniel</creatorcontrib><creatorcontrib>Raynal, Noël J. M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huot, Marielle</au><au>Caron, Maxime</au><au>Richer, Chantal</au><au>Djibo, Rahinatou</au><au>Najmanovich, Rafael</au><au>St-Onge, Pascal</au><au>Sinnett, Daniel</au><au>Raynal, Noël J. M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2021-11-01</date><risdate>2021</risdate><volume>88</volume><issue>5</issue><spage>845</spage><epage>856</epage><pages>845-856</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><abstract>Purpose
Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Recently, we have demonstrated that the heart failure drug, proscillaridin A, produced anticancer effects with specificity toward MYC expressing leukemia cells. We also reported that decitabine, a hypomethylating drug, synergizes with proscillaridin A in colon cancer cells. Here, we investigated whether proscillaridin A exhibits epigenetic and anticancer activity against eRMS RD cells, overexpressing MYC oncogene, and its combination with decitabine.
Methods
We investigated the anticancer effects of proscillaridin A in eRMS RD cells in vitro. In response to drug treatment, we measured growth inhibition, cell cycle arrest, loss of clonogenicity and self-renewal capacity. We further evaluated the impact of proscillaridin A on MYC expression and its downstream transcriptomic effects by RNA sequencing. Then, we measured protein expression of epigenetic regulators and their associated chromatin post-translational modifications in response to drug treatment. Chromatin immunoprecipitation sequencing data sets were coupled with transcriptomic results to pinpoint the impact of proscillaridin A on gene pathways associated with specific chromatin modifications. Lastly, we evaluated the effect of the combination of proscillaridin A and the DNA demethylating drug decitabine on eRMS RD cell growth and clonogenic potential.
Results
Clinically relevant concentration of proscillaridin A (5 nM) produced growth inhibition, cell cycle arrest and loss of clonogenicity in eRMS RD cells. Proscillaridin A produced a significant downregulation of MYC protein expression and inhibition of oncogenic transcriptional programs controlled by MYC, involved in cell replication. Interestingly, significant reduction in total histone 3 acetylation and on specific lysine residues (lysine 9, 14, 18, and 27 on histone 3) was associated with significant protein downregulation of a series of lysine acetyltransferases (KAT3A, KAT3B, KAT2A, KAT2B, and KAT5). In addition, proscillaridin A produced synergistic growth inhibition and loss of clonogenicity when combined with the approved DNA demethylating drug decitabine.
Conclusion
Proscillaridin A produces anticancer and epigenetic effects in the low nanomolar range and its combination with decitabine warrants further investigation for the treatment of eRMS.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>34331108</pmid><doi>10.1007/s00280-021-04339-6</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-4241-6800</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0344-5704 |
| ispartof | Cancer chemotherapy and pharmacology, 2021-11, Vol.88 (5), p.845-856 |
| issn | 0344-5704 1432-0843 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2557232201 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | 5-aza-2'-deoxycytidine Acetylation Acetylation - drug effects Anticancer properties Antineoplastic Combined Chemotherapy Protocols - pharmacology Antitumor activity Cancer Cancer Research Cell cycle Cell Line, Tumor Cell Self Renewal - drug effects Cell self-renewal Chromatin Colon Colon cancer Congestive heart failure Decitabine - administration & dosage Deoxyribonucleic acid DNA Drug Repositioning Epigenetics Evaluation Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene sequencing Histones Histones - metabolism Humans Immunoprecipitation Investigations Leukemia Lysine Lysine - metabolism Medicine Medicine & Public Health Muscles Myc protein Neoplasm Proteins Oncology Original Article Pharmacology/Toxicology Post-translation Promoter Regions, Genetic - drug effects Proscillaridin - administration & dosage Proscillaridin - pharmacology Protein expression Proteins Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Rhabdomyosarcoma Rhabdomyosarcoma, Embryonal - drug therapy Rhabdomyosarcoma, Embryonal - genetics Rhabdomyosarcoma, Embryonal - pathology Skeletal muscle Transcription Transcriptomics |
| title | Repurposing proscillaridin A in combination with decitabine against embryonal rhabdomyosarcoma RD cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T20%3A58%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Repurposing%20proscillaridin%20A%20in%20combination%20with%20decitabine%20against%20embryonal%20rhabdomyosarcoma%20RD%20cells&rft.jtitle=Cancer%20chemotherapy%20and%20pharmacology&rft.au=Huot,%20Marielle&rft.date=2021-11-01&rft.volume=88&rft.issue=5&rft.spage=845&rft.epage=856&rft.pages=845-856&rft.issn=0344-5704&rft.eissn=1432-0843&rft_id=info:doi/10.1007/s00280-021-04339-6&rft_dat=%3Cproquest_cross%3E2577919612%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2577919612&rft_id=info:pmid/34331108&rfr_iscdi=true |