Recently triptolide (TPL) has been proved to have the capacity to inhibit the proliferation of multiple myeloma (MM) cells as well as leukemic cells in vitro. In the present study, we found a synergistic effect when TPL was added to dexamethasone to induce apoptosis in MM.1S cells. This combination induced a significantly higher proportion of apoptotic cells compared with those treated with each drug separately. TPL down-regulated the expression of miR142 - 5p and miR181a, which have been shown to inhibit glucocorticoid receptor (GR) expression. MicroRNA mimics and inhibitors inhibited or enhanced the synergistic effect between TPL and dexamethasone in inducing apoptosis in MM.1S cells, suggesting an important role of miR142 - 5p and miR181a in GR regulation by TPL. The in vitro proapoptotic effect of TPL associated with dexamethasone reveals a new lead for further clinical investigation into the treatment of patients with MM with TPL.
[Show abstract][Hide abstract] ABSTRACT: The initial response of lymphoid malignancies to glucocorticoids (GCs) is a critical parameter predicting successful treatment. Although being known as a strong inducer of apoptosis in lymphoid cells for almost a century, the signaling pathways regulating the susceptibility of the cells to GCs are only partly revealed. There is still a need to develop clinical tests that can predict the outcome of GC therapy. In this paper, I discuss important parameters modulating the pro-apoptotic effects of GCs, with a specific emphasis on the microRNA world comprised of small players with big impacts. The journey through the multifaceted complexity of GC-induced apoptosis brings forth explanations for the differential treatment response and raises potential strategies for overcoming drug resistance.
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is a malignant disorder characterized by neoplastic growth of plasma cells in the bone marrow (1). It is suggested to arise by clonal expansion of plasma cells leading to a condition known as monoclonal gammopathy of undetermined significance (MGUS), which may evolve to smouldering myeloma and finally to symptomatic myeloma (2). Features of symptomatic myeloma are, apart from the production of a clonal protein detected in the serum or urine in most of the cases, the presence of end-organ damage, appearing as anaemia, hypercalcemia, renal impairment, and bone disease (1). This article is protected by copyright. All rights reserved.
European Journal Of Haematology 04/2013; 91(2). DOI:10.1111/ejh.12124 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits PDAC cell growth in vitro and blocks metastatic spread in vivo. Triptolide downregulates heat shock protein 70 (HSP70), a molecular chaperone upregulated in several tumor types. This study investigates the mechanism by which triptolide inhibits HSP70. As microRNAs (miRNAs) are becoming increasingly recognized as negative regulators of gene expression, we tested whether triptolide regulates HSP70 via miRNAs. Here we show that triptolide, as well as quercetin but not gemcitabine, upregulated miR-142-3p in PDAC cells (MIA PaCa-2, Capan-1, and S2-013). Ectopic expression of miR-142-3p inhibited cell proliferation, measured by Electric Cell-substrate Impedance Sensing, and decreased HSP70 expression, measured by real-time PCR and immunoblotting, compared with controls. We demonstrated that miR-142-3p directly binds to the 3'UTR of HSP70, and that this interaction is important as HSP70 overexpression rescued miR-142-3p-induced cell death. We found that miR-142-3p regulates HSP70 independently of heat shock factor 1. Furthermore, Minnelide, a water soluble prodrug of triptolide, induced the expression of miR-142-3p in vivo. This is the first description of an miRNA-mediated mechanism of HSP70 regulation in cancer, making miR-142-3p an attractive target for PDAC therapeutic intervention.
Molecular Cancer Therapeutics 05/2013; 12(7). DOI:10.1158/1535-7163.MCT-12-1231 · 5.68 Impact Factor
Manuel Luis Wolfson, Julieta Aylen Schander, María Victoria Bariani, Fernando Correa, Ana María Franchi
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