[Abstract unavailable

BackgroundMetformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-tumor effects in many cancers, including multiple myeloma (MM); however, the underlying molecular mechanisms have not been clearly elucidated.MethodsThe anti-myeloma effects of metformin were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo NOD-SCID murine xenograft MM model. Cell viability was assessed with CCK8 and cell proliferation was measured by EdU incorporation assay. Cell cycle distribution and apoptosis were examined by flow cytometry. Transmission electron microscopy was used to visualized autophagosomes. Activation of AMPK and inhibition of mTORC1/C2 pathways was assessed by Western blot analysis. RPMI8226 cells and U266 cell lines with AMPK knockdown were generated by transfection with small interfering RNA targeting the AMPK-α1 and α2 subunits using Lipofectamine 2000 reagent.ResultsMetformin effectively inhibited the proliferation of MM cell lines, an effect that was associated with the induction of autophagy and G0/G1 cell cycle arrest, but not apoptosis. Metformin activated AMPK and repressed both mTORC1 and mTORC2 signaling pathways in myeloma cells as well as downstream molecular signaling pathways, such as p-4EBP1 and p-AKT. AMPK activation resulted in direct phosphorylation and activation of tuberous sclerosis complex 2 (TSC2), leading to inhibition of the mammalian target of rapamycin (mTOR). In addition, metformin inhibited myeloma cell growth in an AMPK-dependent manner. The xenograft mouse model further confirmed that metformin inhibited tumor growth by upregulation of AMPK and downregulation of mTOR.ConclusionsMetformin inhibits the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest. Our results suggest that the molecular mechanism involves dual repression of mTORC1 and mTORC2 pathways via AMPK activation. Our study provides a theoretical basis for the development of novel strategies for the treatment of MM using metformin as an already approved and safe drug.

Pinocembrin (PB), the most abundant flavonoid in propolis, has been proven to have neuroprotective property against neurotoxicity in vivo and in vitro. Our recent study demonstrated the neuroprotective effect of PB against Aβ25-35-induced SH-SY5Y neurotoxicity. However, the mechanism as how PB can induce neuroprotection is not known. In the present study, we demonstrate here that PB abrogates the effects of the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) which mimics Parkinson's disease (PD) with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. We found that pretreatment of SH-SY5Y cells with PB significantly reduced the MPP(+)-induced loss of cell viability, the generation of intracellular ROS, apoptotic rate, and the cleavage of caspase-3. PB strikingly inhibited MPP(+)-induced mitochondrial dysfunctions, including lowered membrane potential, decreased Bcl-2/Bax ratio, and the release of cytochrome c. Overall, these results suggest that PB is intimately involved in inhibiting MPP(+)-induced loss of mitochondrial function and induction of apoptosis that contributes toward neuronal survival. These data indicated that PB might provide a valuable therapeutic strategy for the treatment of PD.

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