Abstract D055: Molecular mechanisms of cisplatin-induced toxicity to acute promyelocytic leukemia cells

Abstract

Abstract Purpose: Acute promyelocytic leukemia (APL), is a blood cancer that accounts for about 10% of all acute myloid leukemia cases. Each year in the United States, APL affects about 1,500 patients of all age groups and causes approximately 1.2% of cancer deaths. Research has also pointed out the Hispanic populations have a higher incidence of APL compared to other racial groups. Cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in APL cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. Methods: We used the APL cell line as a model, and applied a variety of molecular tools (cytotoxicity and oxidative stress assays, western blot analysis, flow cytometry, and confocal microscopy) to elucidate cytototoxic mode of action of cisplatin. Results: We found that cisplatin inhibited cell proliferation by a cytotoxicity characterized by DNA-adduct formation, oxidative stress, cell cycle arrest, stress signaling and apoptosis in APL cells. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases (cdks) in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity by modulating p38MAPK pathway in APL cells. Conclusion: Overall the findings from this study provide novel targets of cisplatin mode of action that may be very useful in designing of new APL drugs. Citation Format: Paul Tchounwou, Sanjay Kumar, Andrea Brown. Molecular mechanisms of cisplatin-induced toxicity to acute promyelocytic leukemia cells [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D055.