Exploring the potential of pharmacological inhibition of the enzymes squalene epoxidase, SQLE, and 7-dehydrocholesterol reductase, DHCR7, as sensitizers to chemotherapy in acute myeloid leukemia.

• Grant number: 24/06733-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Bruna Aparecida dos Santos Ormrod
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute myeloid leukemia (AML) is a complex and heterogeneous hematologic neoplasm, characterized by uncontrolled proliferation of myeloid cells in the bone marrow. The standard treatment includes intensive induction chemotherapy with anthracycline and cytarabine (Ara-C), but high relapse rates underscore the need for new therapeutic strategies. Previous studies report that cholesterol plays a crucial role in tumor progression, and its dysregulated metabolism may contribute to chemotherapy resistance. In this context, statins, inhibitors of HMG-CoA reductase, the limiting enzyme in cholesterol biosynthesis, have been evaluated as chemotherapy sensitizers. However, studies demonstrate complications related to the continuous use of statins, especially in elderly patients. Our group has shown that high expression of the genes SQLE and DHCR7 is associated with unfavorable prognosis in AML patients treated with chemotherapy. In this project, we aim to evaluate the effects of selective inhibition of SQLE and DHCR7 enzymes on the survival and proliferation of leukemic cells, as well as their interaction with conventional chemotherapeutic agents such as cytarabine (Ara-C) and anthracyclines (daunorubicin and idarubicin). Therapeutic effects will be assessed in vitro through viability and cell death assays, which will be accompanied by quantification of intracellular cholesterol and expression of genes involved in cholesterol metabolism. It is expected that inhibition of these enzymes will improve chemotherapy response, offering a potential new treatment strategy for AML patients.