Autophagy and glycogen synthase kinase-3 (GSK3) as molecular targets capable of increasing the activity of drugs used in the treatment of myeloid leukemias (acute and chronic)

• Grant number: 12/51215-4
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2013
• End date: December 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Claudia Bincoletto Trindade
• Grantee: Claudia Bincoletto Trindade
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Although autophagy is well known as a physiological process in which the cellular components are degraded by lysosomes, current studies indicate that autophagy can also suppress or increase survival of tumor cells. In leukemia's, autophagy is generally unregulated. In addition, via GSK3, which seems to have a direct relationship with autophagy has been implicated as an important modulator of cell growth MLL leukemia, a subtype of acute leukemia extremely aggressive and of poor prognosis. Therefore, this project aims to understand autophagy and participation of GSK3 signaling pathway in death and/or survival of leukemia cells. For these purposes, using four cell lines with specific molecular features such as HL60 (promyelocytic-like), NB4 (myelocytic leukemia pro-) chronic myeloid leukemia K562 and Lucena (K-562 resistant to vincristine), we intend to evaluate how the modulation of autophagy and GSK-3 pathway alters the response of the first line to cytosine arabinoside, the second line to retinoic acid (ATRA) and the last two lines to imatinib mesylate (IM) and nilotinib. These studies will be performed by testing the cytotoxicity, cell death (labeling with annexin V/PI), cell cycle (using PI), proteins involved in apoptosis and autophagy such as LC3II/I ratio, 1 beclin-1, p62, p53 and Bcl2/Bax by immunoblotting. The methodology will also be used to assess total and phosphorylated GSK3 protein. The cell differentiation will be studied using antibodies specific for mature and progenitor cells such as CD34+ and CD11b+, respectively by flow cytometry. Cell proliferation will be evaluated by clonal culture in presence of specific growth factors to myeloid lineage as GM-CSF. Furthermore, we will evaluate the involvement of caspase-3 in ours groups of studied. We hopefully, with this work, improve a little more knowledge of the impact of autophagy pathway and GSK-3 in the treatment of leukemia focusing the development of new strategies therapeutic. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GIGLI, RAFAEL; PEREIRA, GUSTAVO J. S.; ANTUNES, FERNANDA; BECHARA, ALEXANDRE; GARCIA, DANIEL M.; SPINDOLA, DANIEL G.; JASIULIONIS, MIRIAN G.; CAIRES, ANTONIO C. F.; SMAILI, SORAYA S.; BINCOLETTO, CLAUDIA. The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 107, p. 245-254, JAN 1 2016. (12/51215-4)

GRASSO, SILVINA; PEREIRA, GUSTAVO J. S.; PALMEIRA-DOS-SANTOS, CAROLINE; CALGAROTTO, ANDRANA K.; MARTINEZ-LACACI, ISABEL; ANTONIO FERRAGUT, JOSE; SMAILI, SORAYA S.; BINCOLETTO, CLAUDIA. Autophagy regulates Selumetinib (AZD6244) induced-apoptosis in colorectal cancer cells. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 122, p. 611-618, OCT 21 2016. (12/51215-4)

PALMEIRA-DOS-SANTOS, CAROLINE; PEREIRA, GUSTAVO J. S.; BARBOSA, CHRISTIANO M. V.; JURKIEWICZ, ARON; SMAILI, SORAYA S.; BINCOLETTO, CLAUDIA. Comparative study of autophagy inhibition by 3MA and CQ on Cytarabine-induced death of leukaemia cells. JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, v. 140, n. 6, p. 909-920, JUN 2014. (12/51215-4)

COSTA, MAIRA M.; STILHANO, ROBERTA S.; OLIVEIRA, CARLOS R.; BARBOSA, CHISTIANO M. V.; PEREIRA, GUSTAVO J. S.; PAREDES-GAMERO, EDGAR J.; NAKAIE, CLOVIS R.; SMAILI, SORAYA S.; BINCOLETTO, CLAUDIA. Angiotensin II modulates the murine hematopoietic stem cell and progenitors cocultured with stromal S17 cells. Cell Biology International, v. 45, n. 7, p. 1459-1467, JUL 2021. (12/51215-4)

ANTUNES, F.; PEREIRA, G. J.; JASIULIONIS, M. G.; BINCOLETTO, C.; SMAILI, S. S.. Nutritional shortage augments cisplatin-effects on murine melanoma cells. Chemico-Biological Interactions, v. 281, p. 89-97, FEB 1 2018. (12/51215-4, 13/20073-2)

BINCOLETTO, C.; BECHARA, A.; PEREIRA, G. J. S.; SANTOS, C. P.; ANTUNES, F.; DA-SILVA, J. PEIXOTO; MULER, M.; GIGLI, R. D.; MONTEFORTE, P. T.; HIRATA, H.; et al. Interplay between apoptosis and autophagy, a challenging puzzle: New perspectives on antitumor chemotherapies. Chemico-Biological Interactions, v. 206, n. 2, p. 279-288, NOV 25 2013. (12/51215-4)