Sensitization to Drug Treatment in Precursor B-Cell Acute Lymphoblastic Leukemia Is Not Achieved by Stromal NF-κB Inhibition of Cell Adhesion but by Stromal PKC-Dependent Inhibition of ABC Transporters Activity

Cell adhesion to stromal support and the associated intracellular signaling are central to drug resistance, therefore blocking both has been effective in increasing drug sensitization in leukemia. The stromal Ser/Thr protein kinase C (PKC) has been found to be important for conferring protection to leukemic cells. We aimed at elucidating the intracellular signals connected to cell adhesion and to stromal PKC. We found that NF-κB and Akt were up-regulated in mesenchymal stem cells (MSC) after binding of B-cell acute lymphoblastic leukemia (B-ALL) cells. Nevertheless, Akt inhibition did not induce B-ALL cell detachment. In spite of a clear activation of the NF-κB signaling pathway after B-ALL cell binding (up-regulation NF-κB1/2, and down-regulation of the IKBε and IKBα inhibitors) and an important reduction in cell adhesion after NF-κB inhibition, sensitization to the drug treatment was not observed. This was opposite to the PKC inhibitors Enzastaurin and HKPS, a novel chimeric peptide inhibitor, that were able to increase sensitization to dexamethasone, methotrexate, and vincristine. PLCγ1, Erk1/2, and CREB appear to be related to PKC signaling and PKC effect on drug sensitization since they were contra-regulated by HKPS when compared to dexamethasone-treated cells. Additionally, PKC inhibition by HKPS, but not by Enzastaurin, in MSC reduced the activity of three ABC transporters in leukemic cells treated with dexamethasone, a new indirect mechanism to increase sensitization to drug treatment in B-ALL cells. Our results show the validity of targeting the functional characteristic acquired and modulated during cell-to-cell interactions occurring in the leukemic niche.

ABOUT DISCUSSION QUESTIONS OF DRUG DISEASE DIAGNOSTICS AS AN INTERDISCIPLINARY PROBLEM

The objective of the study – to detect drug sensitization in patients with diffuse dermatoses and complicated allergic anamnesis and to analyze drug spectrum. Materials and methods. 195 patients with drug disease and diffuse dermatoses followed by complicated allergic anamnesis were observed. Drug sensitization was detected by ultrasonic test, agglomeration reaction of leucocytes and rate of erythrocyte sedimentation in the presence of drug. Results. There were detected 23.60% of patients with drug disease, 12.30% with eczema, 11.30% with food toxidermy, 13.80% with psoriasis, 12.80% with atopic dermatitis, 26.20% with other dermatoses. Drug sensitization was detected in 70.80% patients with eczema, 22.70% with food toxidermy, 44.40% with psoriasis, 72.0% with atopic dermatitis, 60.80% with other dermatoses. The most frequently detected sensitization was registered to such drugs as antibiotics (24.60%), cardiovascular (17.40%) and hypotensive (15.40%) medicines, local anaesthetics and analgetics (15.90%), anti-inflammatory (12.30%) medicines, vitamins (13.80%), gastrointestinal medicines (11.30%), corticosteroids (5.10%) and antihistamines (4.10%). Conclusions. 1. Drug sensitization was most frequently detected in patients with eczema, atopic dermatitis and psoriasis. 2. Drug disease was caused in patients with diffuse dermatoses by polysensitization to such drugs as antibiotics (24.60%), cardiovascular (17.40%) and hypotensive (15.40%) medicines, local anaesthetics and analgetics (15.90%), anti-inflammatory medicines (12.30%), vitamins (13.80%), gastrointestinal medicines (11.30%), corticosteroids (5.10%) and antihistamines (4.10%). 3. Drug disease is an interdisciplinary problem because it was detected to the different groups of drugs in patients with diffuse dermatoses both by dermatovenerologists and doctors of all specialties