SELECTIVE SMALL MOLECULE TARGETING OF MCL-1 IN MULTIPLE MYELOMA

Multiple Myeloma (MM) is a deadly blood malignancy, characterized by the uncontrolled proliferation of aberrantly differentiated plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic group of Bcl-2 family proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. In this project, we investigated the effect of the novel Mcl-1 inhibiting agent KS18 on MM cells. We demonstrated the molecules in vitro efficacy as well superior potency towards MM. However, Mcl-1 inhibition by KS18 was associated with a significant reduction of MM cell viability. Moreover, we observed that KS18 was able to induce apoptosis in MM cells in a caspase-dependent manner. Our results propose that targeting Mcl-1 by KS18 may represent a new viable strategy for MM treatment. Furthermore, the present study uncovers the mechanism of action of KS18 and provides the foundation for in vivo assessment of this novel molecule

Discovering Potential in Non-Cancer Medications: A Promising Breakthrough for Multiple Myeloma Patients.

Multiple myeloma (MM) is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse; therefore, advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which are typically a major concern for MM patients. The utilization of pre-existing non-cancer drugs for various myeloma treatments presents a highly efficient and cost-effective strategy, considering their prior preclinical and clinical development. The drugs have shown promising potential in targeting key pathways associated with MM progression and resistance. Thalidomide exemplifies the success that can be achieved through this strategy. This review delves into the current trends, the challenges faced by conventional therapies for MM, and the importance of repurposing drugs for MM. This review highlights a noncomprehensive list of conventional therapies that have potentially significant anti-myeloma properties and anti-neoplastic effects. Additionally, we offer valuable insights into the resources that can help streamline and accelerate drug repurposing efforts in the field of MM

Efficacy of Mcl-1 Inhibitors in Multiple Myeloma Cells Resistant to Bortezomib

Multiple myeloma (MM) is a type of cancer that affects plasma B cells. Patients with MM often experience frequent relapses and can develop resistance to drugs. As a medical researcher, it is important to understand the role of Mcl-1 in preventing intrinsic apoptosis and drug resistance. Mcl-1 belongs to the anti-apoptotic subgroup of Bcl-2 family proteins and plays a crucial role in these processes. Mcl-1 plays a crucial role in driving disease progression and contributing to drug resistance in MM. It has been observed that there is an increased expression of Mcl-1 in 52% of patients with MM during diagnosis, which further rises to 81% during relapse. Thus, researchers are investigating the potential of Mcl-1 inhibitors as a viable treatment option for patients with MM, particularly those who have not responded to previous therapies. Proteasome inhibitor Bortezomib (BTZ) is commonly prescribed as the initial treatment for MM, but unfortunately, patients eventually develop resistance to it. For this study, we created cells that are resistant to BTZ in order to explore the potential mechanisms behind the development of resistance. These cells have been treated with BTZ over a period of 6 months. Regrettably, there are currently no Mcl-1 inhibitors that have been approved by the FDA. However, there are several agents, such as S63845, AZ5991, and VU661013, that are currently undergoing clinical trials. Interestingly, Mcl-1 inhibitors demonstrated effectiveness against sensitive cells but showed a decrease in efficacy against BTZ resistant cells. Our research indicates that cells resistant to BTZ require a higher concentration of Mcl-1 inhibitors in order to undergo cell death. This suggests that these resistant cells may possess a compensatory mechanism that stabilizes the Mcl-1 protein and alters the effectiveness of Mcl-1 inhibitors in treatment. It is worth noting that the anti-apoptotic Bcl-2 protein exhibits heightened expression in resistant cells, even when inhibitors are present. This observation may provide valuable insights into a potential resistance mechanism and calls for further investigation into the compensatory mechanisms that play a crucial role in drug resistance

Bruton\u27s Tyrosine Kinase Targeting in Multiple Myeloma.

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones\u27 hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton\u27s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones\u27 interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM

Autophagy and Apoptosis: Current Challenges of Treatment and Drug Resistance in Multiple Myeloma

Over the past two decades, the natural history of multiple myeloma (MM) has evolved dramatically, owing primarily to novel agents targeting MM in the bone marrow microenvironment (BMM) pathways. However, the mechanisms of resistance acquisition remain a mystery and are poorly understood. Autophagy and apoptosis are tightly controlled processes and play a critical role in the cell growth, development, and survival of MM. Genetic instability and abnormalities are two hallmarks of MM. During MM progression, plasma malignant cells become genetically unstable and activate various signaling pathways, resulting in the overexpression of abnormal proteins that disrupt autophagy and apoptosis biological processes. Thus, achieving a better understanding of the autophagy and apoptosis processes and the proteins that crosslinked both pathways, could provide new insights for the MM treatment and improve the development of novel therapeutic strategies to overcome resistance. This review presents a sufficient overview of the roles of autophagy and apoptosis and how they crosslink and control MM progression and drug resistance. Potential combination targeting of both pathways for improving outcomes in MM patients also has been addressed

Intra-pleural colistin methanesulfonate therapy for pleural infection caused by carbapenem-resistant Acinetobacter baumannii: a successful case report

Infections caused by carbapenem-resistant, Gram-negative bacteria are an increasing clinical challenge, since the antimicrobial treatment options are often limited to colistin methanesulfonate. No data are available regarding the pharmacokinetics of colistin in pleural fluid. We report the case of a 92-year old man with ventilator-associated pneumonia and pleurisy caused by Acinetobacter baumannii and Escherichia coli, which were both multidrug-resistant. After an unsuccessful treatment with intravenous colistin methanesulfonate and imipenem-cilastatin, the addition of intra-pleural colistin methanesulfonate to the intravenous treatment led to a prompt clinical, radiological and microbiological resolution. This is the first report of a successful use of intra-pleural colistin in the literature. The intra-pleural colistin therapy should be considered in selected cases of pleurisy caused by multi-resistant Gram-negative bacteria