The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-κB axis
One of the most lethal malignancies worldwide is colorectal cancer (CRC). Alterations in various signalling pathways, including PI3K-mTOR and NF-κB, have been reported in CRC with subsequent dysregulation of proliferation, apoptosis, angiogenesis and, questionably, autophagy processes. BEZ-235 (dact...
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| Veröffentlicht in: | Molecular biology reports 2020-03, Vol.47 (3), p.2217-2230 |
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| creator | Helmy, Maged. W. Ghoneim, Asser I. Katary, Mohamed A. Elmahdy, Rana K. |
| description | One of the most lethal malignancies worldwide is colorectal cancer (CRC). Alterations in various signalling pathways, including PI3K-mTOR and NF-κB, have been reported in CRC with subsequent dysregulation of proliferation, apoptosis, angiogenesis and, questionably, autophagy processes. BEZ-235 (dactolisib) is a dual PI3K-mTOR inhibitor with potent anti-tumour activity. However, the observed toxicity of BEZ-235 necessitated the termination of its clinical trials. Hence, we aimed to evaluate the potential long-lasting anti-carcinogenic effects of adding diosmin (DIO, a natural NF-κB inhibitor) to BEZ-235 in HCT-116 CRC cells. The median inhibitory concentrations (IC50s) of BEZ-235 and/or DIO were evaluated in the HCT-116 CRC cell line. Caspase-3 activity was assessed colorimetrically, and p-Akt, NF-κB, CD1, VEGF and LC3B levels were assessed by ELISA. Additionally,
LC3-II
and
P62
gene expression were assessed using qRT-PCR. The observed CIs (combination indices) and DRIs (dose reduction indices) confirmed the synergistic effect of DIO and BEZ-235. Co-administration of both drugs either in combination-1 (1 μM for BEZ-235, 250 μM for DIO) or in combination-2 (0.51 μM for BEZ-235 + 101.99 μM for DIO) inhibited the PI3K/Akt/mTOR/NF-κB axis, leading to the induction of apoptosis (via active caspase-3), and the inhibition of proliferation marker (CD1), angiogenesis marker (VEGF), autophagy protein (LC3B) and altered effects on
LC3-II
and
P62
gene expression. Our results reveal the synergistic chemotherapeutic effects of DIO combined with BEZ-235 in the HCT-116 CRC cell line and encourage future preclinical and clinical studies of this combination with reduced BEZ-235 concentrations to avoid its reported toxicity.
Graphic abstract |
| doi_str_mv | 10.1007/s11033-020-05327-4 |
| format | Article |
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LC3-II
and
P62
gene expression were assessed using qRT-PCR. The observed CIs (combination indices) and DRIs (dose reduction indices) confirmed the synergistic effect of DIO and BEZ-235. Co-administration of both drugs either in combination-1 (1 μM for BEZ-235, 250 μM for DIO) or in combination-2 (0.51 μM for BEZ-235 + 101.99 μM for DIO) inhibited the PI3K/Akt/mTOR/NF-κB axis, leading to the induction of apoptosis (via active caspase-3), and the inhibition of proliferation marker (CD1), angiogenesis marker (VEGF), autophagy protein (LC3B) and altered effects on
LC3-II
and
P62
gene expression. Our results reveal the synergistic chemotherapeutic effects of DIO combined with BEZ-235 in the HCT-116 CRC cell line and encourage future preclinical and clinical studies of this combination with reduced BEZ-235 concentrations to avoid its reported toxicity.
Graphic abstract</description><identifier>ISSN: 0301-4851</identifier><identifier>EISSN: 1573-4978</identifier><identifier>DOI: 10.1007/s11033-020-05327-4</identifier><identifier>PMID: 32088816</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Angiogenesis ; Animal Anatomy ; Animal Biochemistry ; Apoptosis ; Autophagy ; Biomedical and Life Sciences ; Caspase-3 ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Clinical trials ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms ; Diosmin - pharmacology ; Dose-Response Relationship, Drug ; Drug Synergism ; Gene expression ; HCT116 Cells ; Histology ; Humans ; Imidazoles - pharmacology ; Life Sciences ; Morphology ; NF-kappa B - metabolism ; NF-κB protein ; Original Article ; Phagocytosis ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt - metabolism ; Quinolines - pharmacology ; Signal transduction ; Signal Transduction - drug effects ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Toxicity ; Tumors ; Vascular endothelial growth factor</subject><ispartof>Molecular biology reports, 2020-03, Vol.47 (3), p.2217-2230</ispartof><rights>Springer Nature B.V. 2020</rights><rights>Molecular Biology Reports is a copyright of Springer, (2020). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-f0ce675be9644f4129252b44ec0db2c159dfea62062bc86c79b1ca06e5097d983</citedby><cites>FETCH-LOGICAL-c375t-f0ce675be9644f4129252b44ec0db2c159dfea62062bc86c79b1ca06e5097d983</cites><orcidid>0000-0003-0375-6762</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/s11033-020-05327-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11033-020-05327-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32088816$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Helmy, Maged. W.</creatorcontrib><creatorcontrib>Ghoneim, Asser I.</creatorcontrib><creatorcontrib>Katary, Mohamed A.</creatorcontrib><creatorcontrib>Elmahdy, Rana K.</creatorcontrib><title>The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-κB axis</title><title>Molecular biology reports</title><addtitle>Mol Biol Rep</addtitle><addtitle>Mol Biol Rep</addtitle><description>One of the most lethal malignancies worldwide is colorectal cancer (CRC). Alterations in various signalling pathways, including PI3K-mTOR and NF-κB, have been reported in CRC with subsequent dysregulation of proliferation, apoptosis, angiogenesis and, questionably, autophagy processes. BEZ-235 (dactolisib) is a dual PI3K-mTOR inhibitor with potent anti-tumour activity. However, the observed toxicity of BEZ-235 necessitated the termination of its clinical trials. Hence, we aimed to evaluate the potential long-lasting anti-carcinogenic effects of adding diosmin (DIO, a natural NF-κB inhibitor) to BEZ-235 in HCT-116 CRC cells. The median inhibitory concentrations (IC50s) of BEZ-235 and/or DIO were evaluated in the HCT-116 CRC cell line. Caspase-3 activity was assessed colorimetrically, and p-Akt, NF-κB, CD1, VEGF and LC3B levels were assessed by ELISA. Additionally,
LC3-II
and
P62
gene expression were assessed using qRT-PCR. The observed CIs (combination indices) and DRIs (dose reduction indices) confirmed the synergistic effect of DIO and BEZ-235. Co-administration of both drugs either in combination-1 (1 μM for BEZ-235, 250 μM for DIO) or in combination-2 (0.51 μM for BEZ-235 + 101.99 μM for DIO) inhibited the PI3K/Akt/mTOR/NF-κB axis, leading to the induction of apoptosis (via active caspase-3), and the inhibition of proliferation marker (CD1), angiogenesis marker (VEGF), autophagy protein (LC3B) and altered effects on
LC3-II
and
P62
gene expression. Our results reveal the synergistic chemotherapeutic effects of DIO combined with BEZ-235 in the HCT-116 CRC cell line and encourage future preclinical and clinical studies of this combination with reduced BEZ-235 concentrations to avoid its reported toxicity.
Graphic abstract</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Angiogenesis</subject><subject>Animal Anatomy</subject><subject>Animal Biochemistry</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Biomedical and Life Sciences</subject><subject>Caspase-3</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Clinical trials</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms</subject><subject>Diosmin - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Gene expression</subject><subject>HCT116 Cells</subject><subject>Histology</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Life Sciences</subject><subject>Morphology</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Original Article</subject><subject>Phagocytosis</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Quinolines - pharmacology</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><issn>0301-4851</issn><issn>1573-4978</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kc1u1DAURi0EotPCC7BAltjQhZnrvzhZtqOWVlQUoWHDxnIcZ8YlsYudIPpqPABLngkP08KOlSXf850r3Q-hFxTeUAC1zJQC5wQYEJCcKSIeoQWVihPRqPoxWgAHSkQt6QE6zPkGAARV8ik64AzquqbVAv1cbx3Od8Gljc-Tt9iEyZPbFAffu2Qm_81h1_fOTjj2eCqwjWPrQ5nEsPvqfMyjDyXX4dOzz4RxiV93xk7FkH17jAu2i12s1oTSqsSHmIrODNiaYF3C1g0DHnxwOFo7p1zwFOfNFvuw9a1_WLSTfLjk75YnX6bluL7-uHx_Tn79OMXmu8_P0JPeDNk9v3-P0Kfzs_Xqglxdv71cnVwRy5WcSA_WVUq2rqmE6AVlDZOsFcJZ6FpmqWy63pmKQcVaW1dWNS21BionoVFdU_Mj9GrvLRf6Ors86Zs4p1BWasYVKChHlYVie8qmmHNyvb5NfjTpTlPQu-r0vjpdqtN_qtOihF7eq-d2dN3fyENXBeB7IJdR2Lj0b_d_tL8Bw6elEw</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Helmy, Maged. 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W. ; Ghoneim, Asser I. ; Katary, Mohamed A. ; Elmahdy, Rana K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-f0ce675be9644f4129252b44ec0db2c159dfea62062bc86c79b1ca06e5097d983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Angiogenesis</topic><topic>Animal Anatomy</topic><topic>Animal Biochemistry</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Biomedical and Life Sciences</topic><topic>Caspase-3</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Clinical trials</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms</topic><topic>Diosmin - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Synergism</topic><topic>Gene expression</topic><topic>HCT116 Cells</topic><topic>Histology</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Life Sciences</topic><topic>Morphology</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Original Article</topic><topic>Phagocytosis</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Quinolines - pharmacology</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Helmy, Maged. W.</creatorcontrib><creatorcontrib>Ghoneim, Asser I.</creatorcontrib><creatorcontrib>Katary, Mohamed A.</creatorcontrib><creatorcontrib>Elmahdy, Rana K.</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>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</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 Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Molecular biology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Helmy, Maged. W.</au><au>Ghoneim, Asser I.</au><au>Katary, Mohamed A.</au><au>Elmahdy, Rana K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-κB axis</atitle><jtitle>Molecular biology reports</jtitle><stitle>Mol Biol Rep</stitle><addtitle>Mol Biol Rep</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>47</volume><issue>3</issue><spage>2217</spage><epage>2230</epage><pages>2217-2230</pages><issn>0301-4851</issn><eissn>1573-4978</eissn><abstract>One of the most lethal malignancies worldwide is colorectal cancer (CRC). Alterations in various signalling pathways, including PI3K-mTOR and NF-κB, have been reported in CRC with subsequent dysregulation of proliferation, apoptosis, angiogenesis and, questionably, autophagy processes. BEZ-235 (dactolisib) is a dual PI3K-mTOR inhibitor with potent anti-tumour activity. However, the observed toxicity of BEZ-235 necessitated the termination of its clinical trials. Hence, we aimed to evaluate the potential long-lasting anti-carcinogenic effects of adding diosmin (DIO, a natural NF-κB inhibitor) to BEZ-235 in HCT-116 CRC cells. The median inhibitory concentrations (IC50s) of BEZ-235 and/or DIO were evaluated in the HCT-116 CRC cell line. Caspase-3 activity was assessed colorimetrically, and p-Akt, NF-κB, CD1, VEGF and LC3B levels were assessed by ELISA. Additionally,
LC3-II
and
P62
gene expression were assessed using qRT-PCR. The observed CIs (combination indices) and DRIs (dose reduction indices) confirmed the synergistic effect of DIO and BEZ-235. Co-administration of both drugs either in combination-1 (1 μM for BEZ-235, 250 μM for DIO) or in combination-2 (0.51 μM for BEZ-235 + 101.99 μM for DIO) inhibited the PI3K/Akt/mTOR/NF-κB axis, leading to the induction of apoptosis (via active caspase-3), and the inhibition of proliferation marker (CD1), angiogenesis marker (VEGF), autophagy protein (LC3B) and altered effects on
LC3-II
and
P62
gene expression. Our results reveal the synergistic chemotherapeutic effects of DIO combined with BEZ-235 in the HCT-116 CRC cell line and encourage future preclinical and clinical studies of this combination with reduced BEZ-235 concentrations to avoid its reported toxicity.
Graphic abstract</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>32088816</pmid><doi>10.1007/s11033-020-05327-4</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-0375-6762</orcidid></addata></record> |
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| ispartof | Molecular biology reports, 2020-03, Vol.47 (3), p.2217-2230 |
| issn | 0301-4851 1573-4978 |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | 1-Phosphatidylinositol 3-kinase AKT protein Angiogenesis Animal Anatomy Animal Biochemistry Apoptosis Autophagy Biomedical and Life Sciences Caspase-3 Cell Proliferation - drug effects Cell Survival - drug effects Clinical trials Colorectal cancer Colorectal carcinoma Colorectal Neoplasms Diosmin - pharmacology Dose-Response Relationship, Drug Drug Synergism Gene expression HCT116 Cells Histology Humans Imidazoles - pharmacology Life Sciences Morphology NF-kappa B - metabolism NF-κB protein Original Article Phagocytosis Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Quinolines - pharmacology Signal transduction Signal Transduction - drug effects TOR protein TOR Serine-Threonine Kinases - metabolism Toxicity Tumors Vascular endothelial growth factor |
| title | The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-κB axis |
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