title: Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk.
abstract: EGFR is a potential therapeutic target for treating bladder cancer, but has not been approved for clinical use yet. Metformin is a widely used antidiabetic drug and has demonstrated interesting anticancer effects on various cancer models, alone or in combination with chemotherapeutic drugs. The efficacy of gefitinib, a well-known EGFR tyrosine kinase inhibitor, combined with metformin was assessed on bladder cancer and underlying mechanisms were explored. This drug combination induced a strong anti-proliferative and anti-colony forming effect and apoptosis in bladder cancer cell lines. Gefitinib suppressed EGFR signaling and inhibited phosphorylation of ERK and Akt. Metformin amplified this inhibitory effect and enhanced gefitinib-induced activation of AMPK signaling pathway. In vivo intravesical treatment of metformin and gefitinib on syngeneic orthotopic mice confirmed the significant inhibitory effect on bladder tumor growth. These two drugs may be an excellent combination for the treatment of bladder cancer through intravesical instillation.
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Tao
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.|TCM and Ethnomedicine Innovation &Development Laboratory, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P. R. China.
authors.forename: Cai-Yun
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Qiongli
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Kwame Oteng
authors.initials: KO
authors.lastname: Darko
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D008687:Metformin; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib