Synergistic Enhancement of Chemotherapy-Induced Cell Death and Antitumor Efficacy against Tumoral T-Cell Lymphoblasts by IMMUNEPOTENT CRP

• Published in: International journal of molecular sciences 2024-07, Vol.25 (14), p.7938
• Main Authors: Rivera-Lazarín, Ana Luisa, Calvillo-Rodríguez, Kenny Misael, Izaguirre-Rodríguez, Mizael, Vázquez-Guillén, José Manuel, Martínez-Torres, Ana Carolina, Rodríguez-Padilla, Cristina
• Format: Article
• Language: English
• Subjects: Analysis; apoptosis; Biochemistry; bone marrow; Breast cancer; Cancer; Cancer therapies; Carfilzomib; Cell death; Chemotherapy; Cytotoxicity; ICRP; Immunotherapy; Lymphoma; Non-Hodgkin's lymphomas; Reactive oxygen species; Smith, Al; synergism; T cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25147938

T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), present significant challenges to treatment due to their aggressive nature and chemoresistance. Chemotherapies remain a mainstay for their management, but the aggressiveness of these cancers and their associated toxicities pose limitations. Immunepotent CRP (ICRP), a bovine dialyzable leukocyte extract, has shown promise in inducing cytotoxicity against various cancer types, including hematological cancers. In this study, we investigated the combined effect of ICRP with a panel of chemotherapies on cell line models of T-ALL and T-LBL (CEM and L5178Y-R cells, respectively) and its impact on immune system cells (peripheral blood mononuclear cells, splenic and bone marrow cells). Our findings demonstrate that combining ICRP with chemotherapies enhances cytotoxicity against tumoral T-cell lymphoblasts. ICRP + Cyclophosphamide (CTX) cytotoxicity is induced through a caspase-, reactive oxygen species (ROS)-, and calcium-dependent mechanism involving the loss of mitochondrial membrane potential, an increase in ROS production, and caspase activation. Low doses of ICRP in combination with CTX spare non-tumoral immune cells, overcome the bone marrow-induced resistance to CTX cell death, and improves the CTX antitumor effect in vivo in syngeneic Balb/c mice challenged with L5178Y-R. This led to a reduction in tumor volume and a decrease in Ki-67 proliferation marker expression and the granulocyte/lymphocyte ratio. These results set the basis for further research into the clinical application of ICRP in combination with chemotherapeutic regimens for improving outcomes in T-cell malignancies.