BACKGROUND AND PURPOSE The expression of P‐glycoprotein (P‐gp), encoded by the multidrug resistance 1 (MDR1) gene, is associated with the emergence of the MDR phenotype in cancer cells. We investigated whether metformin (1,1‐dimethylbiguanide hydrochloride) down‐regulates MDR1 expression in MCF‐7/adriamycin (MCF‐7/adr) cells.EXPERIMENTAL APPROACH MCF‐7 and MCF‐7/adr cells were incubated with metformin and changes in P‐gp expression were determined at the mRNA, protein and functional level. Transient transfection assays were performed to assess its gene promoter activities, and immunoblot analysis to study its molecular mechanisms of action.KEY RESULTS Metformin significantly inhibited MDR1 expression by blocking MDR1 gene transcription. Metformin also significantly increased the intracellular accumulation of the fluorescent P‐gp substrate rhodamine‐123. Nuclear factor‐κB (NF‐κB) activity and the level of IκB degradation were reduced by metformin treatment. Moreover, transduction of MCF‐7/adr cells with the p65 subunit of NF‐κB induced MDR1 promoter activity and expression, and this effect was attenuated by metformin. The suppression of MDR1 promoter activity and protein expression was mediated through metformin‐induced activation of AMP‐activated protein kinase (AMPK). Small interfering RNA methods confirmed that reduction of AMPK levels attenuates the inhibition of MDR1 activation associated with metformin exposure. Furthermore, the inhibitory effects of metformin on MDR1 expression and cAMP‐responsive element binding protein (CREB) phosphorylation were reversed by overexpression of a dominant‐negative mutant of AMPK.CONCLUSIONS AND IMPLICATIONS These results suggest that metformin activates AMPK and suppresses MDR1 expression in MCF‐7/adr cells by inhibiting the activation of NF‐κB and CREB. This study reveals a novel function of metformin as an anticancer agent.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin–lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA–β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to Lmna^G609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin–lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.