ABSTRACT
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.
Subject(s)
Leukemia, Myeloid, Acute , Genes, bcl-2 , BH3 Interacting Domain Death Agonist Protein , Molecular Targeted Therapy , Azacitidine/therapeutic use , Decitabine/therapeutic useABSTRACT
Aim: To investigate the promoting effect of Bcl-2/Bcl-xL inhibitor ABT-737 on apoptosis of gastric cancer cells induced by small molecule Mcl-1 inhibitor UMI-77, and to explore its possible mechanism. Methods: The response of gastric cancer MGC-803 and HGC-27 cells to different concentrations of UMI-77 was detected by MTS assay. In the UMI-77-resistant cell lines, the effect of treatment with UMI-77/ABT-737 alone or in combination on cell viability was detected by MTS assay. The apoptotic rate and the changes of the mitochondrial membrane potential were analyzed by flow cytometry. The cleavage of caspase-9, caspase-3 and PARP-1, as well as the expression level of Bcl-2 family members and IAP proteins, were determined by Western blot. Results: Compared with MGC-803 cells, HGC-27 cells were resistant to UMI-77. Treatment with ABT-737 alone in HGC-27 cells also induced minimal level of cell death. While treatment with both agents induced much greater decreased cell viability. All the dead cells were positive for Annexin V and mitochondrial membrane potential collapsed. Caspase-9, caspase-3 and its substrate PARP-1 were cleaved. All of these proved that the sensitization effect was achieved by activating the mitochondrial apoptotic pathway. Protein levels of XIAP, cIAP1 and cIAP2 decreased after treatment with UMI-77 plus ABT-737. It also resulted in the increase of NOXA and Bcl-2 along with the decline of PUMA and Mcl-1. Conclusions: The combination of UMI-77 and ABT-737 could significantly increase the sensitivity of gastric cancer cells to the Mcl-1 small molecule inhibitor UMI-77.
ABSTRACT
In the past two decades,with the increase of smoking population,more and more people are suffering from small cell lung cancer(SCLC).Besides,it is difficult to find an effective way to cure SCLC,since patience can easily develop drug resistance.On the other hand,with the development of science and technology,people began to study the anti-cancer strategy to increase apoptosis,such as inhibiting the overexpression of survival factors.In these survival factors,BCL-2 family has attracted a lot of attention.BH3-only protein is a member of BCL-2 family and it can directly inhibit the expression of BCL-2 protein,thereby prompting apoptosis.Since the BH3-only protein itself is difficult to become a clinical drug, to find alternatives BH3-only protein-BH3 mimetics is particularly important. Plus, more and more researchers have paid attention on the natural BH3 mimetic since it has less side-effect than artificial BH3 mimetics.To find possible BH3 mimetics,we made a primary screening with this pharma-cophore on a small molecular compounds library via Discovery Studio software. And then MTS assay were introduced to verify the activity of compounds. After that, we use Western Blot and Co-IP meth-ods to test the effect of BH3 mimetics.And finally use CDOCKER to predict the further mechanism on autophagy and apoptosis.In our studies, we found 3 possible BH3 mimetics compounds from 170,000 natural small molecular compounds via pharmacophore-based virtual screening.Furthermore,we dem-onstrated AD23,one of the 3 possible natural BH3 mimetics,induced autophagy and apoptosis simulta-neously in dose-time dependence in SCLC cell line. Finally, we use Molecular Docking to predict the further mechanism on autophagy and apoptosis. We believe our works would provide evidences and clues for the structural optimizing and further study of new drugs in the future.
ABSTRACT
Targeting cell apoptosis is currently the most promising therapy for cancer treatment. The BH3-only protein, which is a member of Bcl-2 family, can bind to the pro-survival members of the family and neutralize their functional activities to induce apoptosis (ie, to isolate pro-apoptotic members of the Bcl-2 family). BH3 mimetics, a kind of small molecule compounds, has the ability to mimic the BH3-only protein to induce apoptosis. The prototype of BH3 mimetics is ABT-737, who can selectively targets on BCL-XL, BCL-2 and BCL-W (but not MCL-1 and A1). ABT-263, a derivative of ABT-737, has a better performance of inducing apoptosis and inhibiting the growth of tumor in clinical trials. At this stage, some presumably BH3 mimetics has entered the clinical stage, while a large part of them is still being characterized and tested. Basing on the mechanism of BH3-only protein, this review summarize a variety of BH3 mimetics which have been widely recognized, and show the latest developments of newly diagnosed BH3 mimetics in the field.
ABSTRACT
Myeloid cell leukemia-1 (MCL-1) protein is one of the key antiapoptotic protein members of the B-cell lymphoma-2 protein family. Overexpression of MCL-1 is closely related to not only tumor progression but also resistance to targeted therapy and traditional chemotherapeutic drug. MCL-1 and its inhibitors have been studied in recent years. The mimetics of MCL-1 endogenous ligand BH3 have resulted in significant breakthroughs. In this study, the research progress on MCL-1 and its inhibitors in hematological malignan-cies is reviewed.