ATORVASTATINA AUMENTA A EFICÁCIA DA CISPLATINA EM CÉLULAS DE CÂNCER DE MAMA ATRAVÉS DA MODULAÇÃO DO METABOLISMO LIPÍDICO
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Data
2021-11-12
Autores
Santos, Diandra Zipinotti dos
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Universidade Federal do Espírito Santo
Resumo
Acquired treatment resistance is a major problem in breast cancer (BC) management, especially aggressive subtypes such as triple-negative-BC (TNBC). Understanding tumor biology and designing new treatments is critical to improving therapeutic efficacy and prognosis. In some cancers, alterations in lipid metabolism, including the accumulation of cholesterol and cholesteryl esters (CE), contribute to tumor progression and development of drug resistance. The present study aimed identify the role of cholesterol metabolism in BC response to cisplatin (CDDP) treatment in the acute setting and in acquired resistance, and if atorvastatin (ATV) can modulate platinum sensitivity. In vitro studies in MCF-7 (Luminal A), MDA-MB-231 (TNBC) and in a developed CDDP-resistant MDA-MB-231 cells (MDACR) were performed using a variety of biochemical and radiometric techniques. Cell viability and cell proliferation were measured through MTT assay and Incucyte, respectively. We demonstrated that CDDP alters cholesterol metabolism in luminal A (MCF -7) and TNBC (MDA-MB-231) cell models and that CDDP in combination with low concentrations of ATV reduces cell proliferation and cell viability more than CDDP alone, especially in MDA-MB-231 cells. MDA-MB-231 cells display elevated levels of CE, LDLR and ACAT1 levels compared to MCF-7 cells, whereas MCF-7 cells had greater HMGCR protein levels compared to MDA-MB-231 cells. The combination of CDDP and ATV dramatically altered cell cholesterol metabolism more in MDA-MB-231 cells than in MCF -7 cells. These results suggest that the increased susceptibility of MDA-MB-231 cells to co-administration of CDDP and ATV compared to MCF -7 cells is related to an increased dependence on CE availability. ATV restored CDDP sensitivity in CDDP-resistant cells, MDACR, which exhibit upregulation of ACAT-1 compared to their parental cells MDA-MB-231. Overall, our data suggest that association of ATV with conventional antineoplastic drugs appears to be beneficial, especially when associated with CDDP for the MDA-MB-231 lineage. Moreover, our data from cell culture-based studies supports upregulation of cholesterol homeostasis as an adaptive response that contributes to aggressiveness and chemotherapy resistance. This adaptive behavior of breast cancer cells and targeting of cholesterol metabolism warrants further preclinical and clinical investigation as a novel strategy to overcome CDDP resistance.
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Palavras-chave
Atorvastatina , cisplatina , câncer de mama