Tu160 - Enhancing Tumor Apoptosis with the Combined Use of Pentoxifylline and Chemotherapeutic Agents in Hodgkin Lymphoma

Pablo Ortiz-Lazareno, PhD – Research Professor, Immunology Division, Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social; Guadalajara, Jalisco, México; Ramón González-Ramella, PhD – Head of Bone Marrow Transplant Unit, Pediatric Hematology and Oncology Department, Hospital Civil de Guadalajara Dr. Juan I. Mechaca; Guadalajara, Jalisco, México.; Alejandro Bravo-Cuellar, PhD – Head of the Immunology Division, Immunology Division, Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social; Guadalajara, Jalisco, México; Susana Del Torro-Arreola, PhD – Research Professor, Instituto de Investigación de Enfermedades Crónico-Degenerativas, Department of Molecular Biology and Genomics, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara; Guadalajara, Jalisco, México.; Adriana Aguilar-Lemarroy, PhD – Research Professor, Immunology Division, Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social; Guadalajara, Jalisco, México; Georgina Hernández-Flores, PhD – Research Professor, Immunology Division, Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social; Guadalajara, Jalisco, México

Abstract Text: Hodgkin Lymphoma (HL) is a B-cell neoplasm predominantly treated with chemotherapy, notably doxorubicin (DOX) and bleomycin (BLM), which are associated with severe adverse effects. Moreover, the cure rate decreases to 75% in advanced-stage patients. Therefore, novel strategies are required to optimize treatment efficacy, minimize adverse effects, and enhance clinical outcomes. Pentoxifylline (PTX) functions as an inhibitor of the NF-κB pathway and enhances chemotherapeutic-induced apoptosis in various cancer cell lines by increasing the expression of proapoptotic genes. Consequently, we propose utilizing PTX as an adjuvant therapy to augment the antitumor effect of chemotherapeutics agents in the HL cell line Hs-445. To this end, we assessed apoptosis, cell cycle, senescence, mitochondrial membrane potential (ΔΨm), and caspase activities through flow cytometry. We found that PTX induces a considerable cell death compared to DOX and BLM, particularly when administered in conjunction with BLM and triple therapy. This cell death primarily occurs via apoptosis, as evidenced by the upregulation of caspases-3, -8, and -9 activity, with a synergistic effect observed when combined with DOX, and BLM. Additionally, PTX induces a loss of ΔΨm, with the most significant impact observed in combination with BLM or triple therapy. Furthermore, PTX abolishes DOX-induced cell arrest in G2, leading to an increase in the percentage of cells in G1. Notably, PTX does not induce senescence and reverses senescence induced by DOX, and BLM. In conclusion, PTX is a potent inducer of apoptosis in HL, augmenting the cytotoxic effects of DOX and BLM while reversing senescence induced by these agents.