Article ; Online: 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.
Molecules (Basel, Switzerland)
2021 Volume 26, Issue 17
Abstract: 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 ...
| Abstract | 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. |
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| MeSH term(s) | ATP-Binding Cassette Transporters/antagonists & inhibitors ; ATP-Binding Cassette Transporters/metabolism ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Adhesion/drug effects ; Drug Screening Assays, Antitumor ; Humans ; NF-kappa B/metabolism ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Precursor Cells, B-Lymphoid/drug effects ; Precursor Cells, B-Lymphoid/metabolism ; Precursor Cells, B-Lymphoid/pathology ; Protein Kinase C/antagonists & inhibitors ; Protein Kinase C/metabolism ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Tumor Cells, Cultured |
| Chemical Substances | ATP-Binding Cassette Transporters ; Antineoplastic Agents ; NF-kappa B ; Protein Kinase Inhibitors ; Protein Kinase C (EC 2.7.11.13) |
| Language | English |
| Publishing date | 2021-09-03 |
| Publishing country | Switzerland |
| Document type | Journal Article |
| ZDB-ID | 1413402-0 |
| ISSN | 1420-3049 ; 1431-5165 ; 1420-3049 |
| ISSN (online) | 1420-3049 |
| ISSN | 1431-5165 ; 1420-3049 |
| DOI | 10.3390/molecules26175366 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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