ascorbic-acid and Blast-Crisis

This study examined whether and how chloroquine inhibits blast progenitor self-renewal (SR) synergistically with phytochemicals or nonsteroidal anti-inflammatory drugs in seven hematological malignant cell lines.. Vitamin C, resveratrol, cyclo-oxygenase inhibitor NS-398 and indomethacin heptyl ester (Ind) were added to cell culture with or without 3 μM chloroquine.. Chloroquine synergistically inhibited blast colony formation in methylcellulose with vitamin C, resveratrol, NS-398 and Ind in one, two, none and one cell lines, respectively, in a total of four out of 28 conditions. Chloroquine synergistically inhibited blast progenitor SR in suspension with vitamin C, resveratrol, NS-398 and Ind in four, six, one and five cell lines, respectively, in a total of 16 out of 28 conditions. In contrast, chloroquine abolished SR inhibition by another agent in four out of 28 conditions.. Chloroquine exerted a marked synergistic inhibition of blast progenitor SR, but not blast colony formation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Blast Crisis; Cell Line, Tumor; Cell Self Renewal; Chloroquine; Hematologic Neoplasms; Humans; Indomethacin; Neoplastic Stem Cells; Nitrobenzenes; Phytochemicals; Resveratrol; Stem Cells; Sulfonamides; Tumor Stem Cell Assay

Imatinib, a BCR/ABL tyrosine kinase inhibitor, has shown remarkable clinical effects in chronic myelogenous leukemia. However, the leukemia cells become resistant to this drug in most blast crisis cases. The transcription factor Nrf2 regulates the gene expression of a number of detoxifying enzymes such as gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in glutathione (GSH) synthesis, via the antioxidant response element (ARE). In this study, we examined the involvement of Nrf2 in the acquisition of resistance to imatinib. Since oxidative stress promotes the translocation of Nrf2 from the cytoplasm to the nucleus, we also examined whether ascorbic acid, a reducing reagent, can overcome the resistance to imatinib by inhibiting Nrf2 activity.. Binding of Nrf2 to the ARE of the gamma-GCS light subunit (gamma-GCSl) gene promoter was much stronger in the imatinib-resistant cell line KCL22/SR than in the parental imatinib-sensitive cell line KCL22. The levels of gamma-GCSl mRNA and GSH were higher in KCL22/SR cells, a finding consistent with the observation of an increase in Nrf2-DNA binding. Addition of a GSH monoester to KCL22 cells resulted in an increase in the IC(50) value of imatinib. In contrast, addition of ascorbic acid to KCL22/SR cells resulted in a decrease in Nrf2-DNA binding and decreases in levels of gamma-GCSl mRNA and GSH. Consistent with these findings, ascorbic acid partly restored imatinib sensitivity to KCL22/SR.. Changes in the redox state caused by antioxidants such as ascorbic acid can overcome resistance to imatinib via inhibition of Nrf2-mediated gene expression.

Topics: Antineoplastic Agents; Ascorbic Acid; Benzamides; Blast Crisis; DNA-Binding Proteins; DNA, Neoplasm; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gene Expression Regulation, Leukemic; Glutamate-Cysteine Ligase; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; NF-E2-Related Factor 2; Oxidative Stress; Piperazines; Protein Transport; Pyrimidines; Regulatory Sequences, Nucleic Acid; RNA, Neoplasm; Trans-Activators

In vitro colony growth was studied on bone marrow cells from 51 patients with myelodysplastic syndromes (MDS), using a cell culture method with the unique feature of daily feeding, in an effort to gain insight into the pathophysiology of MDS and to assess the clinical utility of this cell culture assay. The colony growth pattern of MDS marrow cells is remarkably similar to that of acute myeloid leukemia but quite dissimilar from that of normal marrow, in support of a common pathophysiological mechanism for these two disorders. In particular, L-ascorbic acid (LAA) enhanced colony growth in 30% and suppressed growth in 16% of cases, a finding also similar to that in acute myeloid leukemia, indicating a unique growth requirement which may be explored for therapeutic purposes. Further, these LAA effects have prognostic value, with LAA-sensitive (both LAA-enhanced and LAA-suppressed) cases displaying shorter survivals than LAA-insensitive cases (median survival of 5 months versus 18 months; P = 0.011). This prognostic value is independent of, and more powerful than, bone marrow blasts; the median survival was 18 months for less than 5% bone marrow blasts and 8 months for greater than 5% bone marrow blasts (P = 0.044). These two risk factors can be used together to identify patients with an extremely good or an extremely poor prognosis. This study establishes the clinical usefulness of the LAA effect in MDS as a prognostic factor and provides a new lead to explore in understanding differential biochemical/molecular events and, possibly, a new therapeutic approach to the management of MDS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Refractory; Ascorbic Acid; Blast Crisis; Bone Marrow; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Middle Aged; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis