In contrast to the normal cell, the tumor cell produces vast amounts of extracellular lactate via aerobic glycolysis ( 15) and consequently generates several disturbances in other cells and the tumor microenvironment ( 16), leading to hypoxia, promotion of angiogenesis, and distant metastasis ( 17, 18). Warburg’s research in the 1920s proved that tumor cells require a high income of glucose to maintain their extremely demanded metabolism activity independently of the oxygen levels, a process known as the Warburg effect or aerobic glycolysis ( 12– 14). These therapies have systemic side effects on patients ( 5), high costs ( 6), and rapid development of drug resistance ( 7– 10), which are some of the limitations that reduce their effectiveness ( 11). In such a scenario, the clinical response rates to conventional treatment based on radiation therapy and/or surgery, chemotherapy ( 3), and immunotherapy ( 4) are poor. The use of cervical cancer screening has helped in an early diagnosis of this disease however, there is still a large population in which the disease is diagnosed in locally advanced stages ( 2). Although its incidence has decreased by approximately 40% in the last decade, it currently remains the second leading cause of cancer-related deaths in women, accounting for an estimated 270,000 women’s lives annually ( 1). Our work provides new evidence of TT against cervical cancer as a promising antineoplastic therapy.ĭespite early detection programs, cervical cancer (CC) is a public health problem that still needs to be solved. Also, we show an anti-migratory activity of the TT, suggesting other targets of the drug combination in the late CC stages.ĭiscussion: These results, together with our former studies, conclude that TT inhibits the mTOR pathway leading to cell death by apoptosis. In addition, mTOR and S6K phosphorylated proteins were inhibited in the three cell lines. Results: Through flow cytometry, Western blot, and protein microarray experiments, we found TT-induced apoptosis on HeLa, CaSki, and SiHa through the caspase 3 intrinsic pathway, including the critical proapoptotic proteins BAD, BAX, cytochrome-C, and p21. Methods: In this research, we combined the drugs metformin and sodium oxamate with doxorubicin (named triple therapy or TT) based on their mechanism of action and previous investigation of our group against three CC cell lines. In this scenario, drugs used in other pathologies that have antitumor activity, such as metformin and sodium oxamate, are analyzed. Drug repositioning is a strategy to explore known medicines as treatments for other diseases. Therefore, there is a need to continue with the proposal of new therapies. Existing first-line treatments are not enough to avoid cancer recurrence, progression, or metastasis in locally advanced and advanced stages. Treatments used to manage patients diagnosed in the early stages have excellent results as measured by different clinical outcomes. In particular, in 2020, 30,000 deaths of this type of tumor were reported in Latin America. Introduction: Cervical cancer is a worldwide health problem due to the number of deaths caused by this neoplasm. 6Laboratorio de Genómica Funcional, Unidad de Biomedicina, FES-IZTACALA, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico.5CNC - Center for Neuroscience and Cell Biology, CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.4Laboratorio de Hematopoiesis y Leucemia, Unidad de Investigación, Diferenciación Celular y Cáncer, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Iztapalapa, Mexico.3Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico. 2Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México.1Unidad de Bioquímica Guillermo Soberón Acevedo, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico.Izamary Delgado-Waldo 1,2, Carlos Contreras-Romero 2,3, Sandra Salazar-Aguilar 4, João Pessoa 5, Irma Mitre-Aguilar 1, Verónica García-Castillo 6, Carlos Pérez-Plasencia 3,6* and Nadia Judith Jacobo-Herrera 1*
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