BACKGROUND AND PURPOSEThe 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 APPROACHMCF-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 RESULTSMetformin 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-kB (NF-kB) activity and the level of IkB degradation were reduced by metformin treatment. Moreover, transduction of MCF-7/adr cells with the p65 subunit of NF-kB 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 IMPLICATIONSThese results suggest that metformin activates AMPK and suppresses MDR1 expression in MCF-7/adr cells by inhibiting the activation of NF-kB and CREB. This study reveals a novel function of metformin as an anticancer agent. AbbreviationsACC, acetyl-CoA carboxylase; aicar, 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside; AMPK, adenosine 5′-monophosphate-activated protein kinase; CRE, cAMP-responsive element; CREB, cAMP-responsive element binding protein; DN-AMPK, dominant negative AMPK; GSK-3b, glycogen synthase kinase-3b; MDR1, multidrug resistance 1; NF-kB, nuclear factor-kB; P-gp, P-glycoprotein; PKA, protein kinase A; Rh-123, rhodamine 123; TNF-a, tumour necrosis factor a

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Capsaicin inhibited the EGF-induced invasion and migration of human fibrosarcoma cells via EGFR-dependent FAK/Akt, PKC/Raf/ERK, p38 mitogen-activated protein kinase (MAPK), and AP-1 signaling, leading to the down-regulation of MMP-9 expression. These results indicate the role of capsaicin as a potent anti-metastatic agent, which can markedly inhibit the metastatic and invasive capacity of fibrosarcoma cells.

Edited by Veli-Pekka LehtoKeywords: Metallothionein Invasion Matrix metalloproteinase-9 AP-1 NF-jB a b s t r a c tThe overexpression of metallothionein-2A (MT-2A) is frequently observed in invasive human breast tumors and has been linked with more aggressive breast cancers. MT-2A overexpression led to the induction of MDA-MB-231 breast cancer cell migratory and invasive abilities. The reduction of MT-2A expression through small interfering RNA (siRNA) targeting MT-2A in invasive MDA-MB-231 cells completely inhibited both cell invasion and migration. In addition, the expression of matrix metalloproteinase-9 (MMP-9) and the transcriptional activity of AP-1 and NF-jB were upregulated by MT-2A overexpression. Collectively, our results provide the first demonstration that MT-2A promotes breast cancer cell invasion by upregulating MMP-9 via AP-1 and NF-jB activation. Furthermore, we found that MT-2A silencing can inhibit breast cancer invasiveness.

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Tungtungmadic acid (3-caffeoyl-4-dihydrocaffeoyl quinic acid) is a new chlorogenic acid derivative that was isolated from the Salicornia herbacea. The structure of tungtungmadic acid was determined using chemical and spectral analysis. The antioxidant activity of tungtungmadic acid was evaluated using various antioxidant assays, including free radical scavenging, lipid peroxidation and hydroxyl radical-induced DNA strand breaks assays. Tungtungmadic acid (IC50 = 5.1 microM and 9.3 microM) was found to have higher antioxidant activity in the DPPH scavenging assay as well as in the iron-induced liver microsomal lipid peroxidation system. In addition, the tungtungmadic acid was also effective in protecting the plasmid DNA against strand breakage induced by hydroxyl radicals.