The Differential Effect of Senolytics on SASP Cytokine Secretion and Regulation of EMT by CAFs.

The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.

Modeling Doxorubicin-Induced Cardiomyopathy With Fibrotic Myocardial Damage in Wistar Rats.

Background: Cardiovascular complications, arising after anthracycline chemotherapy, cause a significant deterioration in the life quality and expectancy of those patients who were previously successfully treated for malignant neoplasms. A number of clinical studies have demonstrated that patients with cardiotoxicity manifested during anthracyclines therapy also have extensive fibrotic changes in the cardiac muscle in the long term. Given the lack of an unambiguous understanding of the mechanisms of fibrotic changes formation under doxorubicin treatment in the myocardium, there is the obvious necessity to create a relevant experimental model of chronic doxorubicin-induced cardiomyopathy with fibrotic myocardial lesions and delayed development of diastolic dysfunction. Methods: The study was divided into two stages: first stage (creation of acute doxorubicin cardiomyopathy) - 35 male Wistar rats; second stage (creation of chronic doxorubicin cardiomyopathy) - 40 male Wistar rats. The animals were split into eight groups (two control ones and six experimental ones), which determined the doxorubicin dose (first stage: 25, 20.4, 15 mg/kg; second stage: 5, 10, 15 mg/kg, intraperitoneally) and the frequency of injection. Echocardiographic, hematological, histological, and molecular methods were used to confirm the successful modeling of acute and chronic doxorubicin-induced cardiomyopathy with fibrotic lesions. Results: A model of administration six times every other day with a cumulative dose of doxorubicin 20 mg/kg is suitable for evaluation of acute cardiotoxicity. The 15 mg/kg doxorubicin dose is highly cardiotoxic; what's more, it correlates with progressive deterioration of the clinical condition of the animals after 2 months. The optimal cumulative dose of doxorubicin leads to clinical manifestations confirmed by echocardiographic, histological, molecular changes associated with the development of chronic doxorubicin-induced cardiomyopathy with fibrotic lesions of the left ventricular of the cardiac muscle and ensure long-term survival of animals is 10 mg/kg doxorubicin. A dose of 5 mg/kg of the doxorubicin does not ensure the development of fibrous changes formation. Conclusion: We assume that cumulative dose of 10 mg/kg with a frequency of administration of six times in 2 days can be used to study the mechanisms of anthracycline cardiomyopathy development.

Strategies to Circumvent the Side-Effects of Immunotherapy Using Allogeneic CAR-T Cells and Boost Its Efficacy: Results of Recent Clinical Trials.

Despite the outstanding results of treatment using autologous chimeric antigen receptor T cells (CAR-T cells) in hematological malignancies, this approach is endowed with several constraints. In particular, profound lymphopenia in some patients and the inability to manufacture products with predefined properties or set of cryopreserved batches of cells directed to different antigens in advance. Allogeneic CAR-T cells have the potential to address these issues but they can cause life-threatening graft-versus-host disease or have shorter persistence due to elimination by the host immune system. Novel strategies to create an "off the shelf" allogeneic product that would circumvent these limitations are an extensive area of research. Here we review CAR-T cell products pioneering an allogeneic approach in clinical trials.