Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210 BCR/ABL -expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca 2+ , suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.
Electroporation is used to enhance drug diffusion and gene delivery into the cytosol. The combination of electroporation and cytotoxic drugs, electrochemotherapy (ECT), is used to treat metastatic tumor nodules located at the skin and subcutaneous tissue. The objective response rate following a single session of treatment exceeds 80%, with minimal toxicity for the patients. The efficacy of ECT in the bone and visceral metastasis is currently investigated, and Phase II studies have been completed. ECT has been used to treat skin primary tumors, except melanoma, and is under investigation for locally advanced pancreatic cancer. Early evidence suggests that treatment of tumor nodules with ECT recruits components of the immune system and eliciting a systemic immune response against cancer is a challenging clinical perspective. Considering the proven safety in several different clinical applications electroporation should be viewed as a clinical platform technology with wide perspectives for use in ECT, gene therapy and DNA vaccination.
The inability of myeloid chronic myelogenous leukemia blast crisis (CML-BC) progenitors to undergo neutrophil differentiation depends on suppression of C/EBPα expression through the translation inhibitory activity of the RNA-binding protein hnRNP-E2. Here we show that “oncogene dosage” is a determinant factor for suppression of differentiation in CML-BC. In fact, high levels of p210-BCR/ABL are required for enhanced hnRNP-E2 expression, which depends on phosphorylation of hnRNP-E2 serines 173, 189, and 272 and threonine 213 by the BCR/ABL-activated MAPKERK1/2. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Similarly, pharmacologic inhibition of MAPKERK1/2 activity decreases hnRNP-E2 binding to the 5′UTR of C/EBPα mRNA by impairing hnRNP-E2 phosphorylation and stability. This, in turn, restores in vitro and/or in vivo C/EBPα expression and G-CSF–driven neutrophilic maturation of differentiation-arrested BCR/ABL+ cell lines, primary CML-BCCD34+ patient cells and lineage-negative mouse bone marrow cells expressing high levels of p210-BCR/ABL. Thus, increased BCR/ABL oncogenic tyrosine kinase activity is essential for suppression of myeloid differentiation of CML-BC progenitors as it is required for sustained activation of the MAPKERK1/2-hnRNP-E2-C/EBPα differentiation-inhibitory pathway. Furthermore, these findings suggest the inclusion of clinically relevant MAPK inhibitors in the therapy of CML-BC.
IntroductionBone metastatic disease is a major cause of pain and decreased quality of life in patients with cancer. In addition to systemic therapy and pain control with narcotic analgesics, standard local treatments include palliation with radiation therapy and surgery. However, 20–30 % of patients do not respond to conventional treatments, increasing the interest in alternative therapies. We present the results of a new minimally invasive technique in the treatment of bone metastases.MethodsTwenty-nine patients affected by painful bone metastases were treated with electrochemotherapy (ECT) from July 2009 to July 2011; the mean age was 60 years (range 37–87); 21 patients received a previous ineffective local treatment; the appendicular skeleton was affected in 15 patients while in 14 patients other sites were involved. ECT was performed using the Cliniporator Vitae under fluoroscopy or CT guidance depending on the site of the lesion. Clinical response was assessed using VAS scale and objective tumour response was evaluated according to the MD Anderson criteria for bone metastases.ResultsAll patients well tolerated the procedure and no intraoperative or postoperative complications were observed. At a mean follow-up of 7 months, 24 patients were available for evaluation. 84 % of the patients (20 out of 24) referred improvement of pain ≥50 % with reduction of narcotics consumption. Radiographic evaluation after 3 months in 20 evaluable patients, showed “partial response” in 1 patient, “stable disease” in 17 and “progression” in two cases.DiscussionResults reported in this study demonstrated ECT to be safe and feasible in the treatment of painful bone metastases even when other previous treatments were ineffective. Pain and disease progression control was achieved in the majority of the patients with consequent improvement of quality of life.ConclusionECT should be considered a new feasible tool in the treatment of bone metastases in place or in combination with standard treatments; further developments are required to extend the use of this technique to spine metastases.
Short intense electrical pulses transiently increase the permeability of the cell membrane, an effect known as electroporation. This can be combined with antiblastic drugs for ablation of tumours of the skin and subcutaneous tissue. The aim of this study was to test the efficacy of electroporation when applied to bone and to understand whether the presence of mineralised trabeculae would affect the capability of the electric field to porate the membrane of bone cells. Different levels of electrical field were applied to the femoral bone of rabbits. The field distribution and modelling were simulated by computer. Specimens of bone from treated and control rabbits were obtained for histology, histomorphometry and biomechanical testing. After seven days, the area of ablation had increased in line with the number of pulses and/or with the amplitude of the electrical field applied. The osteogenic activity in the ablated area had recovered by 30 days. Biomechanical testing showed structural integrity of the bone at both times. Electroporation using the appropriate combination of voltage and pulses induced ablation of bone cells without affecting the recovery of osteogenic activity. It can be an effective treatment in bone and when used in combination with drugs, an option for the treatment of metastases.
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