The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells

In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34(+) samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34(+) samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients

Propriedades químicas e biológicas de solo de tabuleiro cultivado com cana-de-açúcar com e sem queima da palhada

Foram comparados dois sistemas de colheita dos canaviais: com queima prévia (Cana Queimada) e com espalhamento da palha na superfície (Cana Crua), em área cedida pela Linhares Agropecuária S.A., Linhares (ES). O solo foi classificado como Podzólico Amarelo de textura arenosa/média, originado de materiais da Formação Barreiras. Após seis anos de cultivo da cana-de-açúcar (1989-1994), foram avaliados a distribuição dos nutrientes, as frações humificadas e o carbono da biomassa microbiana. O sistema Cana Crua promoveu incrementos nos teores de carbono, na profundidade de 0-20 cm, e de magnésio em relação ao sistema Cana Queimada, o qual, por sua vez, apresentou maiores teores de potássio e fósforo. Com a adição da palha, percebeu-se o predomínio não só da fração humina e da fração ácidos fúlvicos, mas também de carbono imobilizado na biomassa microbiana, principalmente nos primeiros 5 cm, com maiores valores na estação chuvosa (novembro)