title: Reduction behavior induced by HL010183, a metformin derivative against the growth of cutaneous squamous cell carcinoma.
abstract: Metformin is a biguanide widely prescribed as a first-line antidiabetic drug in type 2 diabetes mellitus patients. Animal and cellular studies support that metformin has a strong anti-proliferative effect on various cancers. Herein, we report that metformin derivative, HL010183 significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which in turn is associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. Enhanced apoptotic cell death and an increase in Bax: Bcl2 ratio supported the tumor growth reduction. The mechanism of the drug effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Reduced enhancement of NFkB transcriptional target proteins, iNOS/COX-2 together with decreased phosphorylation of NFkB inhibitory protein IKBa were also observed. Further, AKT signaling activation was evaluated by the reduced phosphorylation at Ser473. In addition, a concomitant decrease in mTOR signaling pathway was also estimated from the reduced phosphorylation at mTOR regulatory proteins p70S6K and 4E-BP-1. Along with this, decreased phosphorylation of GSK3b, which is carried out by AKT kinases was also observed. Overall results suggested that HL010183 interrupt SCC growth via NFkB and mTOR signaling pathways.
authors.affiliation: Department of Dermatology, Affiliated Hospital of Hebei University of Engineering Handan 056029, China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Miao
authors.affiliation: Department of Dermatology, Affiliated Hospital of Hebei University of Engineering Handan 056029, China.
authors.forename: Baoguo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Affiliated Hospital of Hebei University of Engineering Handan 056029, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Dermatology, Affiliated Hospital of Hebei University of Engineering Handan 056029, China.
authors.forename: Xike
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Affiliated Hospital of Hebei University of Engineering Handan 056029, China.
authors.forename: Gui-Jing
authors.initials: GJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008687:Metformin / Q000031:analogs & derivatives*; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin
keywords: HL010183; Metformin; apoptosis; cutaneous squamous cell