RESUMO
Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.
Assuntos
Humanos , Antineoplásicos/uso terapêutico , Apoptose , beta Catenina/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Coenzima A Ligases/metabolismo , Leucemia Mieloide Aguda/metabolismo , Lipoilação , Prognóstico , Via de Sinalização WntRESUMO
ABSTRACT Background: Older patients with acute myeloid leukemia are particularly difficult to treat, as they have a high risk of comorbidities, poor performance status and less tolerability to chemotherapy, as well as a more aggressive disease biology, responsible for the resistance to treatment. There is a need to explore novel therapeutic agents that are more effective and tolerable. Venetoclax, a BCL-2 inhibitor is a promising agent, as BCL-2 overexpression is present in 84% of acute myeloid leukemia patients at diagnosis and 95% of patients at relapse and has been associated with leukemia cell survival, chemotherapy resistance and poor prognosis. Objective: To review the available data about venetoclax in acute myeloid leukemia and how it can influence the treatment in older patients. Methods: Using the Pubmed database, we selected 29 articles published within the last 15 years, considering preclinical and clinical trials and review studies that combined venetoclax with acute myeloid leukemia. Results: Venetoclax has demonstrated promising results in preclinical and clinical trials, especially in patients with poor prognosis and the IDH mutation, with an excellent side-effect profile. However, resistance seems to develop rapidly with venetoclax monotherapy, because of antiapoptotic escape mechanisms. Conclusions: While the results with the use of venetoclax seem encouraging, it is not likely that targeting a single pathway will result in long-term disease control. The solution includes the use of combined therapy to block resistance mechanisms and enhance apoptosis, by reducing MCL-1, increasing BIM or inhibiting the complex IV in the mitochondria.
Assuntos
Leucemia Mieloide Aguda , Genes bcl-2 , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3 , Terapia de Alvo Molecular , Azacitidina/uso terapêutico , Decitabina/uso terapêuticoRESUMO
Objective To investigate the effects of gemcitabine and ABT-199 on proliferation inhibition and apoptosis induction of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) cell line SUP-B15, and to explore its synergistic mechanism. Methods SUP-B15 cells in logarithmic growth phase were treated with gemcitabine (0.025 and 0.050 μmol/L), ABT-199 (0, 0.5, 1.0, 2.0, 4.0, 8.0 μmol/L) or two drugs for 24 h. Cell proliferation was detected by CCK-8 method, apoptosis was detected by flow cytometry (FCM), mitochondrial membrane potential was detected by JC-1 method, and expression of mitochondrial apoptosis pathway-related protein was analyzed by Western blot. Results The 50 % inhibitory concentration (IC50) of SBT-B15 cells treated with ABT-199 for 24 h was (4.13±0.89) μmol/L. However, gemcitabine (0.025, 0.050 μmol/L) significantly enhanced the inhibitory effect of ABT-199 on proliferation of SUP-B15 cells, the IC50 values were (2.23 ±0.73) and (1.15 ±0.45) μmol/L, respectively. The results of FCM assay showed that compared with the monotherapy group [(7.33±1.54)%], 0.025 umol/L gemcitabine combined with ABT-199 (1.0 and 2.0 μmol/L) acted on SUP-B15 cells for 24 h, the proportions of apoptotic cells were (32.42±1.45) %and (44.33±1.86) %, the difference was statistically significant (F=70.78, P<0.001);compared with the monotherapy group [(9.60 ±2.76) %], 0.05 μmol/L gemcitabine combined with ABT-199 (1.0 and 2.0 μmol/L) acted on SUP-B15 cells for 24 h, the proportion of apoptotic cells increased to (47.63 ± 3.81) % and (58.73 ±4.33) %, respectively, and the difference was statistically significant (F= 79.21, P<0.001). The JC-1 experiment showed that treated with ABT-199 and gemcitabine for 12 h, the percentage of depolarizing cell was significantly higher than that in single agent group, and the difference was statistical significant (P<0.001). Western blot showed that the anti-apoptotic proteins bcl-2, bcl-xL and Mcl-1 decreased after treated by gemcitabine combined with ABT-199 for 12 h. Conclusion Gemcitabine could enhance the proliferation inhibition and induce apoptosis of Ph+ALL cells by ABT-199, and its mechanism may be related to down-regulation of anti-apoptosis-related proteins.