Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling
Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can b...
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| Veröffentlicht in: | Toxicology in vitro 2018-10, Vol.52, p.306-313 |
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| creator | Hanif, Farina Perveen, Kahkashan Malhi, Saima M. Jawed, Huma Simjee, Shabana U. |
| description | Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can be used in combination therapy with low doses of standard drugs. Verapamil (VP) a known antihypertensive drug has been shown to enhance the activity of bis-chloroethylnitrosourea (BCNU), a drug used to treat GBM. Since, TMZ has replaced BCNU as the standard GBM chemotherapy; therefore, we aimed to study in vitro interaction of VP and TMZ against GBM. Anti-proliferative and apoptotic activities were studied using MTT, TUNEL assay and DAPI staining. Synergy was assessed using combination index method. Apoptotic markers were evaluated by RT-PCR, and immunocytochemistry. Both VP and TMZ significantly inhibited the growth of U87 cells in dose dependent manner. The combine effect of TMZ with VP was synergistic with a CDI value of |
| doi_str_mv | 10.1016/j.tiv.2018.07.001 |
| format | Article |
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•Combination of temozolomide and verapamil synergistically inhibited the growth of U87 glioblastoma cells.•Growth inhibitory activity of Temozolomide and verapamil was related to increased apoptosis.•Combination of TMZ and VP increased apoptosis by increasing ratio of Bax to Bcl-2 expression.•Combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.</description><identifier>ISSN: 0887-2333</identifier><identifier>EISSN: 1879-3177</identifier><identifier>DOI: 10.1016/j.tiv.2018.07.001</identifier><identifier>PMID: 30003979</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antihypertensives ; Apoptosis ; Bcl-2 protein ; Central nervous system ; Chemotherapy ; Drugs ; Glioblastoma ; Glioblastoma multiforme ; Growth inhibition ; Immunocytochemistry ; Polymerase chain reaction ; Temozolmide ; Temozolomide ; Tumors ; Verapamil</subject><ispartof>Toxicology in vitro, 2018-10, Vol.52, p.306-313</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Science Ltd. Oct 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-133fc15f42df05b22a7e500b24686d3f6aa1474587bd18802c70b749f5d205df3</citedby><cites>FETCH-LOGICAL-c381t-133fc15f42df05b22a7e500b24686d3f6aa1474587bd18802c70b749f5d205df3</cites><orcidid>0000-0003-3643-4225 ; 0000-0001-9675-842X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.tiv.2018.07.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30003979$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hanif, Farina</creatorcontrib><creatorcontrib>Perveen, Kahkashan</creatorcontrib><creatorcontrib>Malhi, Saima M.</creatorcontrib><creatorcontrib>Jawed, Huma</creatorcontrib><creatorcontrib>Simjee, Shabana U.</creatorcontrib><title>Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling</title><title>Toxicology in vitro</title><addtitle>Toxicol In Vitro</addtitle><description>Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can be used in combination therapy with low doses of standard drugs. Verapamil (VP) a known antihypertensive drug has been shown to enhance the activity of bis-chloroethylnitrosourea (BCNU), a drug used to treat GBM. Since, TMZ has replaced BCNU as the standard GBM chemotherapy; therefore, we aimed to study in vitro interaction of VP and TMZ against GBM. Anti-proliferative and apoptotic activities were studied using MTT, TUNEL assay and DAPI staining. Synergy was assessed using combination index method. Apoptotic markers were evaluated by RT-PCR, and immunocytochemistry. Both VP and TMZ significantly inhibited the growth of U87 cells in dose dependent manner. The combine effect of TMZ with VP was synergistic with a CDI value of <1. Combination of TMZ and VP increased the ratio of Bax to Bcl-2 expression and thus shifted the equilibrium of cells towards apoptosis. Our findings suggest that the synergistic growth inhibition that was observed in combination treatment group may in part relate to increase in apoptosis. The combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.
•Combination of temozolomide and verapamil synergistically inhibited the growth of U87 glioblastoma cells.•Growth inhibitory activity of Temozolomide and verapamil was related to increased apoptosis.•Combination of TMZ and VP increased apoptosis by increasing ratio of Bax to Bcl-2 expression.•Combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.</description><subject>Antihypertensives</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Central nervous system</subject><subject>Chemotherapy</subject><subject>Drugs</subject><subject>Glioblastoma</subject><subject>Glioblastoma multiforme</subject><subject>Growth inhibition</subject><subject>Immunocytochemistry</subject><subject>Polymerase chain reaction</subject><subject>Temozolmide</subject><subject>Temozolomide</subject><subject>Tumors</subject><subject>Verapamil</subject><issn>0887-2333</issn><issn>1879-3177</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9kU9v1DAQxS0EotuFD8AFWeLSS9KxncSOOKGKUqRKvQBXy_GflVdOHGyn0vLpcbWFAwcuM6PRb55G7yH0jkBLgAzXx7b4x5YCES3wFoC8QDsi-NgwwvlLtAMheEMZYxfoMucjAPSCwmt0werIRj7u0PTDJrWq2Qe8xmKX4lWxGas6NIfg4xRULnFW2DrntdInHB0udo6_YoizNxZPJzxHswVV_HLAao1ricVrnP1hUaHu3qBXToVs3z73Pfp--_nbzV1z__Dl682n-0YzQUpDGHOa9K6jxkE_Uaq47QEm2g1iMMwNSpGOd73gkyFCANUcJt6NrjcUeuPYHl2dddcUf242Fzn7rG0IarFxy5ICB8rGvpY9-vAPeoxbqu9WipBBME7GrlLkTOkUc07WyTX5WaWTJCCfApBHWQOQTwFI4LIGUG_ePytv02zN34s_jlfg4xmw1YpHb5PM2ttFW-OT1UWa6P8j_xvL3ZbU</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>Hanif, Farina</creator><creator>Perveen, Kahkashan</creator><creator>Malhi, Saima M.</creator><creator>Jawed, Huma</creator><creator>Simjee, Shabana U.</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3643-4225</orcidid><orcidid>https://orcid.org/0000-0001-9675-842X</orcidid></search><sort><creationdate>20181001</creationdate><title>Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling</title><author>Hanif, Farina ; Perveen, Kahkashan ; Malhi, Saima M. ; Jawed, Huma ; Simjee, Shabana U.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-133fc15f42df05b22a7e500b24686d3f6aa1474587bd18802c70b749f5d205df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Antihypertensives</topic><topic>Apoptosis</topic><topic>Bcl-2 protein</topic><topic>Central nervous system</topic><topic>Chemotherapy</topic><topic>Drugs</topic><topic>Glioblastoma</topic><topic>Glioblastoma multiforme</topic><topic>Growth inhibition</topic><topic>Immunocytochemistry</topic><topic>Polymerase chain reaction</topic><topic>Temozolmide</topic><topic>Temozolomide</topic><topic>Tumors</topic><topic>Verapamil</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hanif, Farina</creatorcontrib><creatorcontrib>Perveen, Kahkashan</creatorcontrib><creatorcontrib>Malhi, Saima M.</creatorcontrib><creatorcontrib>Jawed, Huma</creatorcontrib><creatorcontrib>Simjee, Shabana U.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Toxicology in vitro</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hanif, Farina</au><au>Perveen, Kahkashan</au><au>Malhi, Saima M.</au><au>Jawed, Huma</au><au>Simjee, Shabana U.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling</atitle><jtitle>Toxicology in vitro</jtitle><addtitle>Toxicol In Vitro</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>52</volume><spage>306</spage><epage>313</epage><pages>306-313</pages><issn>0887-2333</issn><eissn>1879-3177</eissn><abstract>Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can be used in combination therapy with low doses of standard drugs. Verapamil (VP) a known antihypertensive drug has been shown to enhance the activity of bis-chloroethylnitrosourea (BCNU), a drug used to treat GBM. Since, TMZ has replaced BCNU as the standard GBM chemotherapy; therefore, we aimed to study in vitro interaction of VP and TMZ against GBM. Anti-proliferative and apoptotic activities were studied using MTT, TUNEL assay and DAPI staining. Synergy was assessed using combination index method. Apoptotic markers were evaluated by RT-PCR, and immunocytochemistry. Both VP and TMZ significantly inhibited the growth of U87 cells in dose dependent manner. The combine effect of TMZ with VP was synergistic with a CDI value of <1. Combination of TMZ and VP increased the ratio of Bax to Bcl-2 expression and thus shifted the equilibrium of cells towards apoptosis. Our findings suggest that the synergistic growth inhibition that was observed in combination treatment group may in part relate to increase in apoptosis. The combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.
•Combination of temozolomide and verapamil synergistically inhibited the growth of U87 glioblastoma cells.•Growth inhibitory activity of Temozolomide and verapamil was related to increased apoptosis.•Combination of TMZ and VP increased apoptosis by increasing ratio of Bax to Bcl-2 expression.•Combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30003979</pmid><doi>10.1016/j.tiv.2018.07.001</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-3643-4225</orcidid><orcidid>https://orcid.org/0000-0001-9675-842X</orcidid></addata></record> |
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| subjects | Antihypertensives Apoptosis Bcl-2 protein Central nervous system Chemotherapy Drugs Glioblastoma Glioblastoma multiforme Growth inhibition Immunocytochemistry Polymerase chain reaction Temozolmide Temozolomide Tumors Verapamil |
| title | Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling |
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