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Combined treatment with glucagon-like peptide-1 receptor agonist exendin-4 and metformin attenuates breast cancer growth
Cancer is a major cause of death in patients with diabetes. Incretin therapy has received much attention because of its tissue-protective effects. We have previously reported an anti-breast cancer effect of glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4). An anti-cancer effect of metformin...
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Published in: | Diabetology international 2022-07, Vol.13 (3), p.480-492 |
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description | Cancer is a major cause of death in patients with diabetes. Incretin therapy has received much attention because of its tissue-protective effects. We have previously reported an anti-breast cancer effect of glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4). An anti-cancer effect of metformin is well recognized. Therefore, we examined the effect of combined treatment with Ex-4 and metformin in breast cancer cells. In human breast cancer cell lines MCF-7, MDA-MB-231, and KPL-1, 0.1–10 mM metformin significantly reduced the cell number in growth curve analysis in a dose-dependent manner. Furthermore, combined treatment with 0.1 mM metformin and 10 nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In a bromodeoxyuridine (BrdU) assay, Ex-4 or metformin significantly decreased breast cancer cell proliferation and further reduction of BrdU incorporation was observed by combined treatment with Ex-4 and metformin, which suggested that Ex-4 and metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed among Ex-4-treated breast cancer cells, apoptotic cells were clearly detected among metformin-treated breast cancer cells by apoptosis assays. Furthermore, metformin decreased BCL-2 expression in MCF-7 cells. In vivo experiments using a xenograft model showed that Ex-4 and metformin significantly decreased the breast tumor weight and Ki67-positive proliferative cancer cells, and metformin reduced the serum insulin level in mice. These data suggested that Ex-4 and metformin attenuated cell proliferation and metformin induced apoptosis in breast cancer cells. Combined treatment of Ex-4 and metformin may be an optional therapy to inhibit breast cancer progression. |
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Incretin therapy has received much attention because of its tissue-protective effects. We have previously reported an anti-breast cancer effect of glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4). An anti-cancer effect of metformin is well recognized. Therefore, we examined the effect of combined treatment with Ex-4 and metformin in breast cancer cells. In human breast cancer cell lines MCF-7, MDA-MB-231, and KPL-1, 0.1–10 mM metformin significantly reduced the cell number in growth curve analysis in a dose-dependent manner. Furthermore, combined treatment with 0.1 mM metformin and 10 nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In a bromodeoxyuridine (BrdU) assay, Ex-4 or metformin significantly decreased breast cancer cell proliferation and further reduction of BrdU incorporation was observed by combined treatment with Ex-4 and metformin, which suggested that Ex-4 and metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed among Ex-4-treated breast cancer cells, apoptotic cells were clearly detected among metformin-treated breast cancer cells by apoptosis assays. Furthermore, metformin decreased BCL-2 expression in MCF-7 cells. In vivo experiments using a xenograft model showed that Ex-4 and metformin significantly decreased the breast tumor weight and Ki67-positive proliferative cancer cells, and metformin reduced the serum insulin level in mice. These data suggested that Ex-4 and metformin attenuated cell proliferation and metformin induced apoptosis in breast cancer cells. Combined treatment of Ex-4 and metformin may be an optional therapy to inhibit breast cancer progression.</description><identifier>ISSN: 2190-1678</identifier><identifier>EISSN: 2190-1686</identifier><identifier>DOI: 10.1007/s13340-021-00560-z</identifier><identifier>PMID: 35693999</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Agonists ; Antidiabetics ; Apoptosis ; Bcl-2 protein ; Breast cancer ; Bromodeoxyuridine ; Cell growth ; Cell number ; Cell proliferation ; Diabetes ; Diabetes mellitus ; DNA biosynthesis ; Endocrinology ; GLP-1 receptor agonists ; Glucagon ; Glucagon-like peptide 1 ; Insulin ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metformin ; Original ; Original Article ; Peptides ; Tumor cell lines ; Tumors ; Xenografts</subject><ispartof>Diabetology international, 2022-07, Vol.13 (3), p.480-492</ispartof><rights>The Japan Diabetes Society 2021</rights><rights>The Japan Diabetes Society 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-5daf70f0a43c60d7fc14e80a94cca309ac80c9edf8dc9e7918b8c93c3d91bb9f3</citedby><cites>FETCH-LOGICAL-c599t-5daf70f0a43c60d7fc14e80a94cca309ac80c9edf8dc9e7918b8c93c3d91bb9f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174406/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174406/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35693999$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanaka, Yuki</creatorcontrib><creatorcontrib>Iwaya, Chikayo</creatorcontrib><creatorcontrib>Kawanami, Takako</creatorcontrib><creatorcontrib>Hamaguchi, Yuriko</creatorcontrib><creatorcontrib>Horikawa, Tsuyoshi</creatorcontrib><creatorcontrib>Shigeoka, Toru</creatorcontrib><creatorcontrib>Yanase, Toshihiko</creatorcontrib><creatorcontrib>Kawanami, Daiji</creatorcontrib><creatorcontrib>Nomiyama, Takashi</creatorcontrib><title>Combined treatment with glucagon-like peptide-1 receptor agonist exendin-4 and metformin attenuates breast cancer growth</title><title>Diabetology international</title><addtitle>Diabetol Int</addtitle><addtitle>Diabetol Int</addtitle><description>Cancer is a major cause of death in patients with diabetes. Incretin therapy has received much attention because of its tissue-protective effects. We have previously reported an anti-breast cancer effect of glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4). An anti-cancer effect of metformin is well recognized. Therefore, we examined the effect of combined treatment with Ex-4 and metformin in breast cancer cells. In human breast cancer cell lines MCF-7, MDA-MB-231, and KPL-1, 0.1–10 mM metformin significantly reduced the cell number in growth curve analysis in a dose-dependent manner. Furthermore, combined treatment with 0.1 mM metformin and 10 nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In a bromodeoxyuridine (BrdU) assay, Ex-4 or metformin significantly decreased breast cancer cell proliferation and further reduction of BrdU incorporation was observed by combined treatment with Ex-4 and metformin, which suggested that Ex-4 and metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed among Ex-4-treated breast cancer cells, apoptotic cells were clearly detected among metformin-treated breast cancer cells by apoptosis assays. Furthermore, metformin decreased BCL-2 expression in MCF-7 cells. In vivo experiments using a xenograft model showed that Ex-4 and metformin significantly decreased the breast tumor weight and Ki67-positive proliferative cancer cells, and metformin reduced the serum insulin level in mice. These data suggested that Ex-4 and metformin attenuated cell proliferation and metformin induced apoptosis in breast cancer cells. Combined treatment of Ex-4 and metformin may be an optional therapy to inhibit breast cancer progression.</description><subject>Agonists</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Breast cancer</subject><subject>Bromodeoxyuridine</subject><subject>Cell growth</subject><subject>Cell number</subject><subject>Cell proliferation</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>DNA biosynthesis</subject><subject>Endocrinology</subject><subject>GLP-1 receptor agonists</subject><subject>Glucagon</subject><subject>Glucagon-like peptide 1</subject><subject>Insulin</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Metformin</subject><subject>Original</subject><subject>Original Article</subject><subject>Peptides</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>2190-1678</issn><issn>2190-1686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kctuFDEQRS0EItGQH2CBLLFhYyi3--UNEhqFhxSJDawtt13d49BtD7abhHw9HiYMjwXeVEn31C2XLiFPObzkAN2rxIWogUHFGUDTArt7QM4rLoHxtm8fnvquPyMXKV1DebXk0LWPyZloWimklOfkdhuWwXm0NEfUeUGf6Y3LOzrNq9FT8Gx2X5DucZ-dRcZpRFP6EOlBdClTvEVvnWc11d7SBfMY4uI81TmjX3XGRIdiXUijvcFIpxhu8u4JeTTqOeHFfd2Qz28vP23fs6uP7z5s31wx00iZWWP12MEIuhamBduNhtfYg5a1MVqA1KYHI9GOvS2lk7wfeiOFEVbyYZCj2JDXR9_9OixoTTkw6lnto1t0_K6CdupvxbudmsI3JXlX19AWgxf3BjF8XTFltbhkcJ61x7AmVbVdI3vR8r6gz_9Br8MafTnvQNVQiQO5IdWRMjGkFHE8fYaDOmSrjtmqkq36ma26K0PP_jzjNPIryQKII5CK5CeMv3f_x_YHgxKzgg</recordid><startdate>20220701</startdate><enddate>20220701</enddate><creator>Tanaka, Yuki</creator><creator>Iwaya, Chikayo</creator><creator>Kawanami, Takako</creator><creator>Hamaguchi, Yuriko</creator><creator>Horikawa, Tsuyoshi</creator><creator>Shigeoka, Toru</creator><creator>Yanase, Toshihiko</creator><creator>Kawanami, Daiji</creator><creator>Nomiyama, Takashi</creator><general>Springer Nature Singapore</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20220701</creationdate><title>Combined treatment with glucagon-like peptide-1 receptor agonist exendin-4 and metformin attenuates breast cancer growth</title><author>Tanaka, Yuki ; 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Incretin therapy has received much attention because of its tissue-protective effects. We have previously reported an anti-breast cancer effect of glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4). An anti-cancer effect of metformin is well recognized. Therefore, we examined the effect of combined treatment with Ex-4 and metformin in breast cancer cells. In human breast cancer cell lines MCF-7, MDA-MB-231, and KPL-1, 0.1–10 mM metformin significantly reduced the cell number in growth curve analysis in a dose-dependent manner. Furthermore, combined treatment with 0.1 mM metformin and 10 nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In a bromodeoxyuridine (BrdU) assay, Ex-4 or metformin significantly decreased breast cancer cell proliferation and further reduction of BrdU incorporation was observed by combined treatment with Ex-4 and metformin, which suggested that Ex-4 and metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed among Ex-4-treated breast cancer cells, apoptotic cells were clearly detected among metformin-treated breast cancer cells by apoptosis assays. Furthermore, metformin decreased BCL-2 expression in MCF-7 cells. In vivo experiments using a xenograft model showed that Ex-4 and metformin significantly decreased the breast tumor weight and Ki67-positive proliferative cancer cells, and metformin reduced the serum insulin level in mice. These data suggested that Ex-4 and metformin attenuated cell proliferation and metformin induced apoptosis in breast cancer cells. Combined treatment of Ex-4 and metformin may be an optional therapy to inhibit breast cancer progression.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>35693999</pmid><doi>10.1007/s13340-021-00560-z</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Agonists Antidiabetics Apoptosis Bcl-2 protein Breast cancer Bromodeoxyuridine Cell growth Cell number Cell proliferation Diabetes Diabetes mellitus DNA biosynthesis Endocrinology GLP-1 receptor agonists Glucagon Glucagon-like peptide 1 Insulin Medicine Medicine & Public Health Metabolic Diseases Metformin Original Original Article Peptides Tumor cell lines Tumors Xenografts |
title | Combined treatment with glucagon-like peptide-1 receptor agonist exendin-4 and metformin attenuates breast cancer growth |
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