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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorFERNANDES, Jennifer Marx
dc.contributor.authorJANDREY, Elisa Helena Farias
dc.contributor.authorKOYAMA, Fernanda Christtanini
dc.contributor.authorLEITE, Katia Ramos Moeira
dc.contributor.authorCAMARGO, Anamaria Aranha
dc.contributor.authorCOSTA, Erico Tosoni
dc.contributor.authorPEREZ, Rodrigo Oliva
dc.contributor.authorASPRINO, Paula Fontes
dc.identifier.citationDISEASES OF THE COLON & RECTUM, v.63, n.7, p.918-926, 2020
dc.description.abstractBACKGROUND: Neoadjuvant chemoradiation for locally advanced rectal cancer combining 5-fluorouracil with radiation increases tumor regression compared with radiation alone. However, it occurs at the cost of significant treatment-related toxicity. Patients with rectal cancer using metformin have been associated with improved response to radiotherapy. OBJECTIVE: The purpose of this study was to evaluate the radiosensitizing effects of metformin in vitro and in vivo and compare it with a standard combination of radiation/5-fluorouracil. DESIGN: Colorectal cancer cell lines SW480, HT29, and HCT116 were used as models. Cell viability was compared under treatments with radiation, radiation/5-fluorouracil, metformin, radiation/metformin, and radiation/5-fluorouracil/metformin. Nude mice were injected subcutaneously with SW480 cells and treated for 1 week with radiation/5-fluorouracil, metformin, radiation/metformin, or radiation/5-fluorouracil/metformin. Tumor volume was evaluated for 4 weeks after treatment completion. The phosphorylation status of key proteins of the PI3K/Akt/mTOR pathway was determined by immunoblots. SETTINGS: This was an experimental study conducted in vitro and in vivo. PATIENTS: Animal models/cell lines were used. MAIN OUTCOME MEASURES: The end point was to investigate how metformin compares with 5-fluorouracil as a radiosensitizer. RESULTS: All cell lines significantly decreased cell viability after treatment with radiation/metformin when compared with radiation alone. Radiation/metformin was superior to radiation/5-fluorouracil in SW480 (37% vs 74%; p < 0.001). In HT29 and in HCT116, radiation/metformin was inferior to radiation/5-fluorouracil (40.0% vs 13.8%, p < 0.001 and 40.0% vs 7.0%, p < 0.001), mainly because of increased 5-fluorouracil toxicity (<= 20% of cell viability). In vivo assays indicated that radiation/metformin treatment was comparable with radiation/5-fluorouracil (557 vs 398 mm(3); p > 0.05) and that the addition of metformin to the standard radiation/5-fluorouracil did not improve tumor response (349 mm(3); p > 0.05). Metformin exerted strong PI3K/Akt/mTOR pathway inactivation effects after 24-hour exposure (increasing pAMPK, p < 0.01; decreasing pAkt, p < 0.01; and pS6, p <0.05). LIMITATIONS: In vitro and in vivo chemoradiation regimens cannot be directly translated to human delivery methods. CONCLUSIONS: Metformin enhances tumor response to radiation in vitro and in vivo. Metformin is an attractive alternative radiosensitizing agent to be considered in future studies/trials. See Video Abstract at
dc.description.sponsorshipLudwig Institute for Cancer Research
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
dc.description.sponsorshipCoordination for the Improvement of Higher Education Personnel
dc.relation.ispartofDiseases of the Colon & Rectum
dc.subjectRadiosensitizing agenteng
dc.subject.othershort-course radiotherapyeng
dc.titleMetformin as an Alternative Radiosensitizing Agent to 5-Fluorouracil During Neoadjuvant Treatment for Rectal Cancereng
dc.rights.holderCopyright LIPPINCOTT WILLIAMS & WILKINSeng
dc.description.conferencedateJUN 01-05, 2019
dc.description.conferencelocalCleveland, OH
dc.description.conferencenameAnnual Scientific Meeting of the American-Society-of-Colon-and-Rectal-Surgeons (ASCRS)
dc.subject.wosGastroenterology & Hepatologyeng
dc.type.categoryarticle; proceedings papereng
dc.type.versionpublishedVersioneng, Jennifer Marx:Hosp Sirio Libanes, Sao Paulo, Brazil, Elisa Helena Farias:Hosp Sirio Libanes, Sao Paulo, Brazil, Fernanda Christtanini:Hosp Sirio Libanes, Sao Paulo, Brazil, Katia Ramos Moeira:Hosp Sirio Libanes, Sao Paulo, Brazil, Anamaria Aranha:Hosp Sirio Libanes, Sao Paulo, Brazil, Erico Tosoni:Hosp Sirio Libanes, Sao Paulo, Brazil, Paula Fontes:Hosp Sirio Libanes, Sao Paulo, Brazil
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