Cancer Research and Treatment (2024)

High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy
Jung Eun Lee, Ji Hee Lim, Yong Kil Hong, Seung Ho Yang
Cancer Res Treat. 2018;50(4):1331-1342. Published online January 10, 2018
DOI: https://doi.org/10.4143/crt.2017.466
AbstractCancer Research and Treatment (3)PDFSupplementary MaterialPubReaderePub
Purpose
The purpose of the study is to investigate the efficacy of combined treatment with temozolomide (TMZ) and metformin for glioblastoma (GBM) in vitro and in vivo.
Materials and Methods
We investigated the efficacy of combined treatment with TMZ and metformin using cell viability and apoptosis assays. A GBM orthotopic mice model was established by inoculation of 5×105 U87 cells and treatedwith metformin, TMZ, and the combination for 4weeks. Western blotting and immunofluorescence of tumor specimens were analyzed to investigate AMP-activated protein kinase (AMPK) and AKT pathway.
Results
The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mammalian target of rapamycin phosphorylation, AKT phosphorylation, and p53 expression. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days for control, metformin treatment (2 mg/25 g/day or 10 mg/25 g/day), TMZ treatment (15 mg/kg/day), combination treatment with low-dose metformin and TMZ, and combination treatment with high-dose metformin and TMZ, respectively. Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin and TMZ.
Conclusion
The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.

Citations

Citations to this article as recorded byCancer Research and Treatment (7)

  • Survival Impact of Combined Biguanide and Temozolomide in Glioblastoma Preclinical Models: A Systematic Review and Meta-Analysis
    Marcio Yuri Ferreira, Eloísa Bittencurt Thomaz de Assis, Savio Batista, Lucca B. Palavani, Gabriel Verly, Eduardo Mendes Corrêa, Lucas Pari Mitre, Jessica Sales de Oliveira, Raphael Bertani, Daniel Antunes Moreno, Allan Dias Polverini
    World Neurosurgery.2024; 183: 239.CrossRef
  • Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme
    Corina Tamas, Flaviu Tamas, Attila Kovecsi, Alina Cehan, Adrian Balasa
    International Journal of Molecular Sciences.2024; 25(10): 5482.CrossRef
  • Metformin and its potential influence on cell fate decision between apoptosis and senescence in cancer, with a special emphasis on glioblastoma
    Melika Hajimohammadebrahim-Ketabforoush, Alireza Zali, Mohammadreza Shahmohammadi, Amir Ali Hamidieh
    Frontiers in Oncology.2024;[Epub]CrossRef
  • GBM Cells Exhibit Susceptibility to Metformin Treatment According to TLR4 Pathway Activation and Metabolic and Antioxidant Status
    Isabele Fattori Moretti, Antonio Marcondes Lerario, Paula Rodrigues Sola, Janaína Macedo-da-Silva, Mauricio da Silva Baptista, Giuseppe Palmisano, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie
    Cancers.2023; 15(3): 587.CrossRef
  • Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells
    Corinna Seliger, Lisa Rauer, Anne-Louise Wüster, Sylvia Moeckel, Verena Leidgens, Birgit Jachnik, Laura-Marie Ammer, Simon Heckscher, Katja Dettmer, Markus Riemenschneider, Peter Oefner, Martin Proescholdt, Arabel Vollmann-Zwerenz, Peter Hau
    International Journal of Molecular Sciences.2023; 24(4): 3199.CrossRef
  • The Potential Therapeutic Impact of Metformin in GlioblastomaMultiforme
    Mehdi Sanati, Samaneh Aminyavari, Hamid Mollazadeh, Ali Motamed-Sanaye, Bahram Bibak, Elmira Mohtashami, Yong Teng, Amir R. Afshari, Amirhossein Sahebkar
    Current Medicinal Chemistry.2023; 30(7): 857.CrossRef
  • Development and validation of a GC-MS method for determination of metformin in normal brain and in glioblastoma tissues
    Giorgia Ailuno, Sara Baldassari, Alice Balboni, Giuliana Drava, Cristina Spalletti, Elena Tantillo, Michele Mazzanti, Federica Barbieri, Stefano Thellung, Tullio Florio, Gabriele Caviglioli
    Journal of Pharmaceutical and Biomedical Analysis.2023; 234: 115503.CrossRef
  • Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study)
    Wan-Soo Yoon, Jong Hee Chang, Jeong Hoon Kim, Yu Jung Kim, Tae-Young Jung, Heon Yoo, Se-Hyuk Kim, Young-Cho Ko, Do-Hyun Nam, Tae Min Kim, Se Hoon Kim, Sung-Hae Park, Youn Soo Lee, Hyeon Woo Yim, Yong-Kil Hong, Seung Ho Yang
    Discover Oncology.2023;[Epub]CrossRef
  • Targeted c-Myc Inhibition and Systemic Temozolomide Therapy Extend Survival in Glioblastoma Xenografts
    Laxmi Dhungel, Cayla Harris, Lauren Romine, Jan Sarkaria, Drazen Raucher
    Bioengineering.2023; 10(6): 718.CrossRef
  • Could Metformin and Resveratrol Support Glioblastoma Treatment? A Mechanistic View at the Cellular Level
    Raghad Sabaawi Ibrahim, Shahad Sabaawi Ibrahim, Ahmed El-Naas, Lenka Koklesová, Peter Kubatka, Dietrich Büsselberg
    Cancers.2023; 15(13): 3368.CrossRef
  • Dysregulated lipid metabolism in TMZ-resistant glioblastoma: pathways, proteins, metabolites and therapeutic opportunities
    Tzu-Jen Kao, Chien-Liang Lin, Wen-Bin Yang, Hao-Yi Li, Tsung-I Hsu
    Lipids in Health and Disease.2023;[Epub]CrossRef
  • THERAPEUTIC USE OF METFORMIN IN THYROID CANCER
    Fatimah Haitham Fathi, Ammar A. Y. Almulathanon, Jehan A. Mohammad
    Military Medical Science Letters.2022; 91(4): 348.CrossRef
  • Targeting Oncogenic Rewiring of Lipid Metabolism for Glioblastoma Treatment
    Haksoo Lee, Dahye Kim, BuHyun Youn
    International Journal of Molecular Sciences.2022; 23(22): 13818.CrossRef
  • Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway
    Jinbiao Xiong, Gaochao Guo, Lianmei Guo, Zengguang Wang, Zhijuan Chen, Yang Nan, Yiyao Cao, Ruilong Li, Xuejun Yang, Jun Dong, Xun Jin, Weidong Yang, Qiang Huang
    ACS Omega.2021; 6(6): 4289.CrossRef
  • Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma
    Silvia Valtorta, Alessia Lo Dico, Isabella Raccagni, Cristina Martelli, Valentina Pieri, Paolo Rainone, Sergio Todde, Bastian Zinnhardt, Elisabetta De Bernardi, Angela Coliva, Letterio S. Politi, Thomas Viel, Andreas H. Jacobs, Rossella Galli, Luisa Ottob
    Frontiers in Oncology.2021;[Epub]CrossRef
  • Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook
    Kevin Zhai, Manaal Siddiqui, Basma Abdellatif, Alena Liskova, Peter Kubatka, Dietrich Büsselberg
    Cancers.2021; 13(10): 2317.CrossRef
  • Role of Polymeric Local Drug Delivery in Multimodal Treatment of Malignant Glioma: A Review
    Yuan-Yun Tseng, Tai-Yuan Chen, Shih-Jung Liu
    International Journal of Nanomedicine.2021; Volume 16: 4597.CrossRef
  • In Vitro and In Vivo Enhancement of Temozolomide Effect in Human Glioblastoma by Non-Invasive Application of Cold Atmospheric Plasma
    Vikas Soni, Manish Adhikari, Hayk Simonyan, Li Lin, Jonathan H. Sherman, Colin N. Young, Michael Keidar
    Cancers.2021; 13(17): 4485.CrossRef
  • Landscape of the oncogenic role of fatty acid synthase in human tumors
    Xulei Huo, Lairong Song, Da Li, Ke Wang, Yali Wang, Feng Chen, Liwei Zhang, Liang Wang, Junting Zhang, Zhen Wu
    Aging.2021; 13(23): 25106.CrossRef
  • Cetylpyridinium chloride is a potent AMP-activated kinase (AMPK) inducer and has therapeutic potential in cancer
    Sonia A. Allen, Sandipan Datta, Jose Sandoval, Alexey Tomilov, Thomas Sears, Kevin Woolard, James M. Angelastro, Gino A. Cortopassi
    Mitochondrion.2020; 50: 19.CrossRef
  • Metformin treatment decreases the expression of cancer stem cell marker CD44 and stemness related gene expression in primary oral cancer cells
    Shankargouda Patil
    Archives of Oral Biology.2020; 113: 104710.CrossRef
  • Metformin Treatment Sensitizes Human Laryngeal Cancer Cell Line Hep- 2 to 5-Fluorouracil
    Neslisah Barlak, Fatma Sanli, Ozel Capik, Elanur Tuysuz, Elanur Aydın Karatas, Hasan Turkez, Omer Faruk Karatas
    Clinical Cancer Drugs.2020; 7(1): 16.CrossRef
  • An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin
    Marta Calvo Tardón, Eliana Marinari, Denis Migliorini, Viviane Bes, Stoyan Tankov, Emily Charrier, Thomas A McKee, Valérie Dutoit, Pierre-Yves Dietrich, Erika Cosset, Paul R Walker
    Biology.2020; 9(9): 264.CrossRef
  • Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead
    Rashmi R. Shah, Peter D. Stonier
    Journal of Clinical Pharmacy and Therapeutics.2019; 44(1): 6.CrossRef
  • Repurposed Biguanide Drugs in Glioblastoma Exert Antiproliferative Effects via the Inhibition of Intracellular Chloride Channel 1 Activity
    Federica Barbieri, Ivan Verduci, Valentina Carlini, Gianluigi Zona, Aldo Pagano, Michele Mazzanti, Tullio Florio
    Frontiers in Oncology.2019;[Epub]CrossRef
  • DrugR+: A comprehensive relational database for drug repurposing, combination therapy, and replacement therapy
    Yosef Masoudi-Sobhanzadeh, Yadollah Omidi, Massoud Amanlou, Ali Masoudi-Nejad
    Computers in Biology and Medicine.2019; 109: 254.CrossRef
  • Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells
    Alessia Lo Dico, Silvia Valtorta, Luisa Ottobrini, Rosa Maria Moresco
    Frontiers in Oncology.2019;[Epub]CrossRef
  • Repurposing drugs for the treatment of glioma
    Chengming Xu, Yaodong Zhao, Congyan Wu, Lei Li
    Glioma.2019; 2(4): 159.CrossRef
  • Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway
    Chung-Ching Chio, Yu-Ting Tai, Mahendravarman Mohanraj, Shing-Hwa Liu, Shun-Tai Yang, Ruei-Ming Chen
    Phytomedicine.2018; 49: 41.CrossRef
  • Pleiotropic Effects of Metformin on Cancer
    Hans-Juergen Schulten
    International Journal of Molecular Sciences.2018; 19(10): 2850.CrossRef
  • Metformin attenuates cells stemness and epithelial‑mesenchymal transition in colorectal cancer cells by inhibiting the Wnt3a/β‑catenin pathway
    Chu Zhang, Yuchen Wang
    Molecular Medicine Reports.2018;[Epub]CrossRef
  • 15,456View
  • 730Download
  • 31Web of Science
  • 31Crossref
Optimal Timing for the Administration of Capecitabine with Preoperative Chemoradiation for Locally Advanced Rectal Cancer
Young Ju Noh, Won Sik Choi, Jong Hoon Kim, Jin Cheon Kim, Chang Sik Yu, Hee Cheol Kim, Tae Won Kim, Heung Moon Chang, Min Hee Ryu, Seung Do Ahn, Sang-wook Lee, Seong Soo Shin, Jung Eun Lee, Eun Kyung Choi
Cancer Res Treat. 2006;38(1):30-34. Published online February 28, 2006
DOI: https://doi.org/10.4143/crt.2006.38.1.30
AbstractCancer Research and Treatment (9)PDFPubReaderePub
Purpose

Capecitabine is an oral fluoropyrimidine carbamate and it is known as an effective radiosensitizer. Capecitabine and its metabolite reach their peak concentration in the plasma at 1~2 hours after a single oral administration of capecitabine and the levels fall rapidly thereafter. To verify the radiosensitizing effect of capecitabine that is based on such pharmacokinetic characteristics, we performed a retrospective analysis on the optimal timing of capecitabine administration with performing preoperative chemoradiation for locally advanced rectal cancer.

Materials and Methods

Among 171 patients who were treated with preoperative radiotherapy and concurrent capecitabine administration for rectal cancer, 56 patients were administered capecitabine at 1~2 hours before radiotherapy (group A), and at other time in the other 115 patients (group B). Total mesorectal excision was done at 4 to 6 weeks after the completion of chemoradiation. The radiosensitizing effect of capecitabine was evaluated on the basis of the pathological response.

Results

Complete pathological regression of the primary tumor was observed in 12 patients (21.4%) for group A and in 11 patients (9.6%) for group B (p=0.031). Residual disease less than 0.5 cm (a good response) was observed in 19 patients (33.9%) for group A and in 23 patients (20.0%) for group B (p=0.038). On multivariate analysis, the capecitabine ingestion time showed marginal significance.

Conclusion

When performing preoperative chemoradiation for locally advanced rectal cancer, the radiosensitizing effect of capecitabine was enhanced when it was administered 1 hour before radiotherapy.

Citations

Citations to this article as recorded byCancer Research and Treatment (12)

  • Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer
    R Clifford, N Govindarajah, J L Parsons, S Gollins, N P West, D Vimalachandran
    British Journal of Surgery.2018; 105(12): 1553.CrossRef
  • 8,998View
  • 49Download
  • 1Crossref
Cancer Research and Treatment (2024)

References

Top Articles
Latest Posts
Recommended Articles
Article information

Author: Kareem Mueller DO

Last Updated:

Views: 6224

Rating: 4.6 / 5 (66 voted)

Reviews: 89% of readers found this page helpful

Author information

Name: Kareem Mueller DO

Birthday: 1997-01-04

Address: Apt. 156 12935 Runolfsdottir Mission, Greenfort, MN 74384-6749

Phone: +16704982844747

Job: Corporate Administration Planner

Hobby: Mountain biking, Jewelry making, Stone skipping, Lacemaking, Knife making, Scrapbooking, Letterboxing

Introduction: My name is Kareem Mueller DO, I am a vivacious, super, thoughtful, excited, handsome, beautiful, combative person who loves writing and wants to share my knowledge and understanding with you.