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The karyotypically silent t(4;14)(p16;q2.3) translocation occurs in approximately 15% of all multiple myeloma (MM) cases, and results in the ectopic expression of fibroblast growth factor receptor 3 (FGFR3). In previous work we overexpressed FGFR3 or the constitutively active FGFR3-TD mutant in an interleukin-6 (IL-6)-dependent murine myeloma cell line, B9. High expression levels of FGFR3 conferred IL-6 independence, increased phosphorylation of STAT3 and upregulated the anti-apoptotic factor bcl-xL. Since bcl-xL can confer chemo-resistance in cancer cells, we hypothesized that FGFR3 overexpression may be sufficient to confer drug resistance to malignant plasma cells. To examine this issue, we tested FGFR3 expressing B9 cells for chemotherapy sensitivity. Melphalan or Doxorubicin both resulted in cell death comparable to controls at low concentrations of drug. In contrast no cell death was observed following exposure of FGFR3 engineered cell lines to Dexamethasone. Believing that this observed Dexamethasone resistance was due to the upregulation of bcl-xL, a bcl-x L antisense oligonucleotide was employed. Upon treatment with this oligonucleotide, FGFR3 expressing B9 cells were rendered sensitive to Dexamethasone. Activated caspase-3 cleaves proteins essential for cell survival, including bcl-x L. To explore the potential of caspase-3 as a cytotoxic molecule in the treatment of MM, the murine myeloma cell line, B9BM1, was transduced with an RU486-inducible caspase-3 retrovirus (B9BM-C3). After induction with RU486, apoptotic cell death of B9BM-C3 cells began by 4 hours and was complete by 48 hours post-induction, while non-transduced cells remained viable. Annexin V staining demonstrated 40%, 78% and 97% apoptotic cell death at 18, 24 and 30 hours post-induction. In co-culture experiments, induced B9BM-C3 cells generated a significant bystander effect. By MTT assay, a mix of 20:80 (B9BM-C3:parental cells) resulted in the death of 80% of the unmodified parental controls. B9BM-C3 cells formed tumors after subcutaneous injection in mice. Early treatment of these mice with RU486 eradicated tumor. Inducing caspase-3 expression in myeloma cells rapidly results in cell death and provides collateral cell damage via a putative bystander effect. These results indicate that therapeutic attempts to induce caspase-3 in myeloma cells may prove useful in the treatment of MM.
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Spotlight on ixazomib: Potential in the treatment of multiple myeloma Article (PDF Available) in Drug Design, Development and Therapy 10(Issue 1) January with 1, Reads. Procaspase-3 Activation to Caspase PC-3, the precursor to caspase-3, consists of a prodomain, a large subunit, and a small subunit (Figure 2A).PC-3 activation to caspase-3 results from proteolysis at Asp9, Asp28, and Asp 26–28 Caspase-3 is a cysteine protease that cleaves over proteins and ultimately leads to apoptotic cell death. 29–31 The conversion of PC-3 to caspase-3 is a Cited by: 2. Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of Cited by: Abstract. Effective treatment for myeloma began in the early s with the introduction of melphalan and cyclophosphamide (1).During the past four decades, clinicians have found that the most effective drugs for the treatment of myeloma belong to the following pharmacologic classes: alkylating agents (melphalan, cyclophosphamide, 1,3-bis-[2-chloroethyl]nitrosurea [BCNU]), topoisomerase II Author: Terry H. Landowski, William S. Dalton, Sydney E. Salmon.
Podar K, Raab MS, Zhang J, et ing PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LYHCl) Blood, Author: Klaus Podar, Kenneth C. Anderson. Multiple myeloma is the second most common hematologic malignancy, characterized by the proliferation of malignant plasma cells in the bone marrow and excessive production of immunoglobulins [1,2].The clinical outcome of patients with multiple myeloma has been improved in recent decades due to the development of novel therapeutic agents such as the proteasome inhibitors bortezomib Cited by: 4. Recently, the introduction of novel agents, especially the proteasome inhibitor bortezomib (Velcade), thalidomide, and its structural analogue lenalidomide (Revlimid), has changed treatment paradigms for newly diagnosed multiple myeloma (MM), for therapeutic approaches at the time of MM relapse, as well as for maintenance therapy after stem cell transplantation (1–11).Cited by: Aim: To ascertain the function of miRNAa in hepatocellular carcinoma (HCC) and to assess its use as a therapeutic agent through the analysis of pre-clinical and clinical trials. Discussion: Multiple studies found that miRNAa was down-regulated in the majority of human HCC samples and subsequently had a tumour suppressor role via the inhibition of a number of target genes essential for.
Targetting the ubiquitin pathway is an attractive strategy for cancer therapy. The inhibitor of the ubiquitin-like molecule NEDD8 pathway, MLN (Pevonedistat) is in Phase II clinical by: 7. Multiple myeloma is a malignant disease of plasma cells that manifests as one or more of lytic bone lesions, monoclonal protein in the blood or urine, and disease in the bone marrow. Treatment for myeloma has changed beyond recognition in the past decade, and now includes state of the art supportive treatment and infusional chemotherapy courses, followed for younger patients by high-dose. Multiple myeloma (MM) is the second most common hematologic malignancy and, although the development of novel agents has improved survival of patients, to date, it remains incurable. Thus, newer and more effective therapeutic strategies against this malignancy are necessary. Plant extracts play an important role in anti-tumor drug discovery. For this reason, in the investigation of novel Cited by: 5. The therapeutic approach to hematological malignancies is based on chemotherapy using anticancer drugs, but such treatment has serious side effects, and some complications (e.g. serious infection and bleeding) associated with use of these drugs can be by: 1.