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AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF‐β/Smad signalling in hepatocellular carcinoma
Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, w...
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| Published in: | Journal of cellular and molecular medicine 2021-10, Vol.25 (20), p.9805-9813 |
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| container_end_page | 9813 |
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| container_title | Journal of cellular and molecular medicine |
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| creator | Chung, Jeff Yat‐Fai Chan, Max Kam‐Kwan Tang, Philip Chiu‐Tsun Chan, Alex Siu‐Wing Chung, Justin Shing‐Yin Meng, Xiao‐Ming To, Ka‐Fai Lan, Hui‐Yao Leung, Kam‐Tong Tang, Patrick Ming‐Kuen |
| description | Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance. |
| doi_str_mv | 10.1111/jcmm.16928 |
| format | article |
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Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.16928</identifier><identifier>PMID: 34514726</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>AANG ; Aged ; Animals ; Antibodies ; Antineoplastic Agents - pharmacology ; Asiatic acid ; Biological Products - pharmacology ; Cancer therapies ; Carcinoma, Hepatocellular ; Cell Line, Tumor ; Chinese medicine ; Cytotoxicity ; Disease Models, Animal ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Enzymes ; Equilibrium ; Glycoproteins ; Hepatocellular carcinoma ; Humans ; Immunohistochemistry ; Laboratory animals ; Liver cancer ; Liver Neoplasms - etiology ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Mice ; Microenvironments ; Middle Aged ; Multidrug resistance ; Multidrug resistant organisms ; Naringenin ; Original ; Proteins ; p‐glycoprotein ; Signal Transduction - drug effects ; Smad protein ; Smad Proteins - metabolism ; Smad3 protein ; Smad7 protein ; Software ; Statistical analysis ; TGF‐β/Smad signalling ; Traditional Chinese medicine ; Transcription ; Transforming Growth Factor beta - metabolism ; Tumor microenvironment ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Journal of cellular and molecular medicine, 2021-10, Vol.25 (20), p.9805-9813</ispartof><rights>2021 The Authors. published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.</rights><rights>2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4488-98d1434ff941121810dff7afeab5e25dfc9fb6f35cf89a63f2ebe670050c1b33</citedby><cites>FETCH-LOGICAL-c4488-98d1434ff941121810dff7afeab5e25dfc9fb6f35cf89a63f2ebe670050c1b33</cites><orcidid>0000-0002-1166-561X ; 0000-0002-7695-2513 ; 0000-0002-3194-3736 ; 0000-0003-4283-9755</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2580834517/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2580834517?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,11562,25753,27924,27925,37012,37013,44590,46052,46476,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34514726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chung, Jeff Yat‐Fai</creatorcontrib><creatorcontrib>Chan, Max Kam‐Kwan</creatorcontrib><creatorcontrib>Tang, Philip Chiu‐Tsun</creatorcontrib><creatorcontrib>Chan, Alex Siu‐Wing</creatorcontrib><creatorcontrib>Chung, Justin Shing‐Yin</creatorcontrib><creatorcontrib>Meng, Xiao‐Ming</creatorcontrib><creatorcontrib>To, Ka‐Fai</creatorcontrib><creatorcontrib>Lan, Hui‐Yao</creatorcontrib><creatorcontrib>Leung, Kam‐Tong</creatorcontrib><creatorcontrib>Tang, Patrick Ming‐Kuen</creatorcontrib><title>AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF‐β/Smad signalling in hepatocellular carcinoma</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>Cancer cells are high in heterogeneity and versatility, which can easily adapt to the external stresses via both primary and secondary resistance. Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance.</description><subject>AANG</subject><subject>Aged</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Asiatic acid</subject><subject>Biological Products - pharmacology</subject><subject>Cancer therapies</subject><subject>Carcinoma, Hepatocellular</subject><subject>Cell Line, Tumor</subject><subject>Chinese medicine</subject><subject>Cytotoxicity</subject><subject>Disease Models, Animal</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Enzymes</subject><subject>Equilibrium</subject><subject>Glycoproteins</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Laboratory animals</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - etiology</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Mice</subject><subject>Microenvironments</subject><subject>Middle Aged</subject><subject>Multidrug resistance</subject><subject>Multidrug resistant organisms</subject><subject>Naringenin</subject><subject>Original</subject><subject>Proteins</subject><subject>p‐glycoprotein</subject><subject>Signal Transduction - drug effects</subject><subject>Smad protein</subject><subject>Smad Proteins - metabolism</subject><subject>Smad3 protein</subject><subject>Smad7 protein</subject><subject>Software</subject><subject>Statistical analysis</subject><subject>TGF‐β/Smad signalling</subject><subject>Traditional Chinese medicine</subject><subject>Transcription</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Tumor microenvironment</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>1582-1838</issn><issn>1582-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>PIMPY</sourceid><recordid>eNp9kU9uEzEUxkcIREthwwGQJTaoUlr_nfGwQIqiNoBaWJC95fHYE0ceO9gzQdlxBLZcg4NwCE6Ch4QKWODNs9738-dnf0XxFMELlNflRvX9BSprzO8Vp4hxPKM1ofePe8QJPykepbSBkJSI1A-LE0IZohUuT4uv8_m75UswB14OY5QOqNBvw-hbYELsRyenCsJOxyxY34HcG2wbxw5EnWwapFca7KwEae917HLHqiw10mVlOjCsNVgtr398_vL92-WHXrYg2c5L5ybRerDWWzkEpZ3Lt0WgZMzHQi8fFw-MdEk_OdazYnV9tVq8nt28X75ZzG9milLOZzVvESXUmJoihBFHsDWmkkbLhmnMWqNq05SGMGV4LUtisG50WUHIoEINIWfFq4Ptdmx63Srth_wNYhttL-NeBGnF34q3a9GFneAMMk55NnhxNIjh46jTIHqbpudIr8OYBGYVxogyiDP6_B90E8aY_2KiOORTLFWmzg-UiiGlqM3dMAiKKXAxBS5-BZ7hZ3-Of4f-TjgD6AB8sk7v_2Ml3i5ubw-mPwHBTbv9</recordid><startdate>202110</startdate><enddate>202110</enddate><creator>Chung, Jeff Yat‐Fai</creator><creator>Chan, Max Kam‐Kwan</creator><creator>Tang, Philip Chiu‐Tsun</creator><creator>Chan, Alex Siu‐Wing</creator><creator>Chung, Justin Shing‐Yin</creator><creator>Meng, Xiao‐Ming</creator><creator>To, Ka‐Fai</creator><creator>Lan, Hui‐Yao</creator><creator>Leung, Kam‐Tong</creator><creator>Tang, Patrick Ming‐Kuen</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1166-561X</orcidid><orcidid>https://orcid.org/0000-0002-7695-2513</orcidid><orcidid>https://orcid.org/0000-0002-3194-3736</orcidid><orcidid>https://orcid.org/0000-0003-4283-9755</orcidid></search><sort><creationdate>202110</creationdate><title>AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF‐β/Smad signalling in hepatocellular carcinoma</title><author>Chung, Jeff Yat‐Fai ; Chan, Max Kam‐Kwan ; Tang, Philip Chiu‐Tsun ; Chan, Alex Siu‐Wing ; Chung, Justin Shing‐Yin ; Meng, Xiao‐Ming ; To, Ka‐Fai ; Lan, Hui‐Yao ; Leung, Kam‐Tong ; Tang, Patrick Ming‐Kuen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4488-98d1434ff941121810dff7afeab5e25dfc9fb6f35cf89a63f2ebe670050c1b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>AANG</topic><topic>Aged</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antineoplastic Agents - 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Targeting of tumour microenvironment (TME) is a new approach and an ideal therapeutic strategy especially for the multidrug resistant cancer. Recently, we invented AANG, a natural compound formula containing traditional Chinese medicine (TCM) derived Smad3 inhibitor Naringenin (NG) and Smad7 activator Asiatic Acid (AA), for rebalancing TGF‐β/Smad signalling in the TME, and its implication on the multidrug resistance is still unexplored. Here, we observed that an equilibrium shift of the Smad signalling in patients with hepatocellular carcinoma (HCC), which was dramatically enhanced in the recurrent cases showing p‐glycoprotein overexpression. We optimized the formula ratio and dosage of AANG that effectively inhibit the proliferation of our unique human multidrug resistant subclone R‐HepG2. Mechanistically, we found that AANG not only inhibits Smad3 at post‐transcriptional level, but also upregulates Smad7 at transcriptional level in a synergistic manner in vitro. More importantly, AANG markedly suppressed the growth and p‐glycoprotein expression of R‐HepG2 xenografts in vivo. Thus, AANG may represent a novel and safe TCM‐derived natural compound formula for overcoming HCC with p‐glycoprotein‐mediated multidrug resistance.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>34514726</pmid><doi>10.1111/jcmm.16928</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-1166-561X</orcidid><orcidid>https://orcid.org/0000-0002-7695-2513</orcidid><orcidid>https://orcid.org/0000-0002-3194-3736</orcidid><orcidid>https://orcid.org/0000-0003-4283-9755</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1582-1838 |
| ispartof | Journal of cellular and molecular medicine, 2021-10, Vol.25 (20), p.9805-9813 |
| issn | 1582-1838 1582-4934 |
| language | eng |
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| source | Wiley_OA刊; ProQuest - Publicly Available Content Database; PubMed Central |
| subjects | AANG Aged Animals Antibodies Antineoplastic Agents - pharmacology Asiatic acid Biological Products - pharmacology Cancer therapies Carcinoma, Hepatocellular Cell Line, Tumor Chinese medicine Cytotoxicity Disease Models, Animal Drug resistance Drug Resistance, Neoplasm - drug effects Drug Synergism Enzymes Equilibrium Glycoproteins Hepatocellular carcinoma Humans Immunohistochemistry Laboratory animals Liver cancer Liver Neoplasms - etiology Liver Neoplasms - metabolism Liver Neoplasms - pathology Mice Microenvironments Middle Aged Multidrug resistance Multidrug resistant organisms Naringenin Original Proteins p‐glycoprotein Signal Transduction - drug effects Smad protein Smad Proteins - metabolism Smad3 protein Smad7 protein Software Statistical analysis TGF‐β/Smad signalling Traditional Chinese medicine Transcription Transforming Growth Factor beta - metabolism Tumor microenvironment Tumors Xenograft Model Antitumor Assays Xenografts |
| title | AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF‐β/Smad signalling in hepatocellular carcinoma |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T09%3A22%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=AANG:%20A%20natural%20compound%20formula%20for%20overcoming%20multidrug%20resistance%20via%20synergistic%20rebalancing%20the%20TGF%E2%80%90%CE%B2/Smad%20signalling%20in%20hepatocellular%20carcinoma&rft.jtitle=Journal%20of%20cellular%20and%20molecular%20medicine&rft.au=Chung,%20Jeff%20Yat%E2%80%90Fai&rft.date=2021-10&rft.volume=25&rft.issue=20&rft.spage=9805&rft.epage=9813&rft.pages=9805-9813&rft.issn=1582-1838&rft.eissn=1582-4934&rft_id=info:doi/10.1111/jcmm.16928&rft_dat=%3Cproquest_pubme%3E2580834517%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c4488-98d1434ff941121810dff7afeab5e25dfc9fb6f35cf89a63f2ebe670050c1b33%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2580834517&rft_id=info:pmid/34514726&rfr_iscdi=true |