The chemotherapeutic regimen melphalan, prednisolone, and thalidomide (MPT) is the standard of care for symptomatic multiple myeloma patients who are not eligible for high dose chemotherapy followed by autologous stem cell therapy. Lenalidomide, a newer thalidomide derivative, is 300 times more potent than thalidomide. Combined therapy using melphalan, prednisolone, and lenalidomide (MPL) is very effective with many advantages. We report here one rare adverse effect, i.e., intrahepatic cholestasis related to lenalidomide, in two patients out of a total of 65 newly diagnosed cases of multiple myeloma receiving MPL regimen in our series. As the use of lenalidomide will increase in the future for multiple myeloma and other diseases, clinicians should be aware of this entity.
Cancer stem cells (CSC) are pool of dedicated undifferentiated cells responsible for maintenance of tumorigenesis. They play a key role by continuing growth and propagation of cancer. These cancer stem cells share many similarities with natural stem cells like self renewal and plasticity of differentiation. Activity of these stem cells is regulated by various paracrine signals. Stem cell activity is dependent on complex interplay between cancer stem cell and its microenvironment called niche. MicroRNAs are newer class of molecules involved in modulating differentiation of stem cells. Cancer stem cells also determine propensity for metastasis of a tumour. They have considerable resistance against conventional chemotherapy or radiation. Therefore pose significant challenge for elimination of tumour. Now days, targeting these stem cells are a new focus of attention in cancer therapeutics.
BackgroundMetformin causes immunomodulation by activation of AMP-kinase and thereby inhibition of mTOR pathway. Metformin reduces disease activity in lupus mouse models.1 A study has shown that its use in lupus patients decreased corticosteroid dose and prevented flares.2 P-glycoprotein expression is linked to drug resistance and increased cytokine production. Metformin inhibits expression of P- Glycoprotein (P-gp) in cancer cells.3 There is scarce data on effect of metformin on P-gp expression and cytokine secretion on immune cells in autoimmune diseases like lupus.ObjectivesTo study the effect of metformin on P-gp expression in PBMCs of lupus patients and its effect on inflammatory cytokines secretion. To determine optimum concentration required for such an effect.MethodsPBMCs of nine lupus patients(Mean age 30 yrs, all females) were cultured using RPMA medium and then stimulated with PMA/ ionomycin, with or without increasing dose of metformin (0.01, 0.1,1,10 mMol/L) for 24 h. Cytokines IL-1b, IL-6, IFN-g and IL-10 were analyzed by ELISA in culture supernatant. Cell viability was independently assessed by MTT assay. P-gp expression was measured in same samples by flow-cytometry.ResultsIn MTT assay viability of cells was maintained across all concentrations of metformin used in this study(figure 1a). Metformin decreased expression of P-gp in PBMCs in dose dependent manner (p=0.003). (figure 1b). In the PBMC cultures with PMA and increasing concentration of metformin, there was decrease in production of pro-inflammatory cytokines: IL-1b (p=0.001), IL-6 (p=0.007) and IFNg (p<0.001) at even the lowest concentration of metformin. There was increase in production of anti-inflammatory cytokine IL-10 (p=0.014). The suppression of IL-1, IL-6, IFNg and increase in IL10 production was dose dependent.Abstract AB0167 – Figure 1a: MTT assay for cell viability (ns) b: P-gp expression with increasing metformin concentration (shown on X axis in mMOL/L), c,d,e,f: cytokine alnalyses of IL-1β, IL-6, IFN-γ and IL-10 resp. In all experiments, PBMCs were stimulated by PMA and Metformin. ***=P<0.01, **=P<0.03ConclusionsMetformin inhibits P-gp expression which is responsible for resistance to action of various drugs including corticosteroids which are cornerstones of treatment in SLE. Metformin thus may help to reduce corticosteroid dose. Anti-inflammatory activity seen in this study is occurring at concentrations which are therapeutically achievable. Plasma levels of metformin at the therapeutic doses commonly used for diabetes are usually around 0.01–0.04 mM/L.4 Present study has demonstrated anti-inflammatory effect of metformin at this concentration. Metformin offers dual advantage which has anti-inflammatory activity and also has a potential to reduce drug resistance to other therapeutic agents.References[1] Lee S-Y, Moon S-J, Kim E-K, et al. Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3. The Journal of Immunology Autho...
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