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      Induction chemotherapy reduces extracellular heat shock protein 72 levels, inflammation, lipoperoxidation and changes insulin sensitivity in children and adolescents newly diagnosed with acute lymphoblastic leukemia

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          Abstract

          Background

          Acute lymphoblastic leukemia (ALL) is associated with higher levels of pro-inflammatory cytokines and oxidative stress. Recently, the levels of extracellular heat shock protein 72 (eHSP72) were found to be elevated in ALL, and its elevation associated with poor prognosis. Therefore, considering the possible role of eHSP72 as a modulator of the immunological system and metabolism, the aim of this study was to describe the response of eHSP72 to the induction phase of chemotherapy, along with metabolic, inflammatory and oxidative stress markers, in children and adolescents newly diagnosed with ALL.

          Methods

          Nineteen patients were recruited and analysed before and after the induction phase of chemotherapy (with 28 days of duration). Blood samples were taken for the analysis of C-reactive protein (CRP), levels of lipoperoxidation, insulin (and HOMA-IR), cortisol, glucose, lipid profile and eHSP72.

          Results

          We found that induction phase of chemotherapy leads to a drop in glucose levels (from 101.79±19 to 75.8±9.7 mg/dL), improvements on inflammation (CRP levels, p<0.01) and oxidative stress (TBARS levels, p<0.01), reduction on eHSP72 (p=0.03) and improved insulin sensitivity (HOMA-IR, p=0.02).

          Conclusion

          Our results indicate that eHSP72 may have an immune and metabolic role and could be used as a marker of the treatment success and metabolic changes in children with ALL.

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          Most cited references48

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          Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications.

          Heat shock proteins (Hsps) are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. We review the current status of the role of Hsp expression in cancer with special emphasis on the clinical setting. Although Hsp levels are not informative at the diagnostic level, they are useful biomarkers for carcinogenesis in some tissues and signal the degree of differentiation and the aggressiveness of some cancers. In addition, the circulating levels of Hsp and anti-Hsp antibodies in cancer patients may be useful in tumor diagnosis. Furthermore, several Hsp are implicated with the prognosis of specific cancers, most notably Hsp27, whose expression is associated with poor prognosis in gastric, liver, and prostate carcinoma, and osteosarcomas, and Hsp70, which is correlated with poor prognosis in breast, endometrial, uterine cervical, and bladder carcinomas. Increased Hsp expression may also predict the response to some anticancer treatments. For example, Hsp27 and Hsp70 are implicated in resistance to chemotherapy in breast cancer, Hsp27 predicts a poor response to chemotherapy in leukemia patients, whereas Hsp70 expression predicts a better response to chemotherapy in osteosarcomas. Implication of Hsp in tumor progression and response to therapy has led to its successful targeting in therapy by 2 main strategies, including: (1) pharmacological modification of Hsp expression or molecular chaperone activity and (2) use of Hsps in anticancer vaccines, exploiting their ability to act as immunological adjuvants. In conclusion, the present times are of importance for the field of Hsps in cancer, with great contributions to both basic and clinical cancer research.
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            Cytogenetics in acute leukemia.

            Cytogenetic analyses in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) have revealed a great number of non-random chromosome abnormalities. In many instances, molecular studies of these abnormalities identified specific genes implicated in the process of leukemogenesis. The more common chromosome aberrations have been associated with specific laboratory and clinical characteristics, and are now being used as diagnostic and prognostic markers guiding the clinician in selecting the most effective therapies. Specific chromosome aberrations and their molecular counterparts have been included in the World Health Organization classification of hematologic malignancies, and together with morphology, immunophenotype and clinical features are used to define distinct disease entities. However, the prognostic importance of less frequent recurrent aberrations in AML and ALL, both primary and secondary, is still to be determined. This review summarizes current views on clinical relevance of major cytogenetic findings in adult AML and ALL.
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              Heat shock proteins: endogenous modulators of apoptotic cell death.

              The highly conserved heat shock proteins (HSPs) accumulate in cells exposed to heat and a variety of other stressful stimuli. HSPs, which function mainly as molecular chaperones, allow cells to adapt to gradual changes in their environment and to survive in otherwise lethal conditions. The events of cell stress and cell death are linked and HSPs induced in response to stress appear to function at key regulatory points in the control of apoptosis. HSPs include antiapoptotic and proapoptotic proteins that interact with a variety of cellular proteins. Their expression level can determine the fate of the cell in response to a death stimulus, and apoptosis-inhibitory HSPs, in particular HSP27 and HSP70, may participate in carcinogenesis. This review summarizes apoptosis-regulatory function of HSPs.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                19 June 2018
                19 June 2018
                : 9
                : 47
                : 28784-28795
                Affiliations
                1 Departamento de Nutrição, Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
                2 Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX) and Laboratory of Cellular Physiology, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
                3 Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil
                Author notes
                Correspondence to: Ana Paula Trussardi Fayh, apfayh@ 123456yahoo.com.br
                Article
                25609
                10.18632/oncotarget.25609
                6033368
                1adb1b0a-d99d-42ab-8349-e9566a68552d
                Copyright: © 2018 Fayh et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 February 2018
                : 19 May 2018
                Categories
                Clinical Research Paper

                Oncology & Radiotherapy
                acute lymphoblastic leukemia,chemotherapy,ehsp72,oxidative stress,glycaemia and inflammation

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