PMID: 25755715Mar 11, 2015Paper

Reduction behavior induced by HL010183, a metformin derivative against the growth of cutaneous squamous cell carcinoma

International Journal of Clinical and Experimental Pathology
Guoying MiaoGui-Jing Liu

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 re...Continue Reading

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