RESUMEN

Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French-American-British subtypes M4 and M5). A 3-fold improvement in survival rates is observed in the parthanatos-positive versus -negative patient groups (hazard ratio [HR] = 0.28-0.37, p = 0.002-0.046). Manipulation of PARP-1 activity in parthanatos-competent cells reveals higher drug sensitivity in cells that have basal PARP-1 levels as compared with those subjected to PARP-1 overexpression or suppression. The same trends are observed in RNA expression databases and support the conclusion that PARP-1 can have optimal levels for favorable chemotherapeutic responses.

Asunto(s)

Leucemia , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Apoptosis , Línea Celular , Leucocitos Mononucleares , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico

RESUMEN

Chimeric antigen receptor (CAR) T cell therapy is a relatively new form of immunotherapy that has had success in treating patients with hematologic malignancies, leading to three recent United States Food and Drug Administration approvals. However, several challenges hinder the widespread use of CAR-T therapy. Here, we review the application of functional nucleic acids such as aptamers and ribozymes as novel tools to improve a variety of steps in CAR-T cell therapy development. We critically examine key studies that highlight the benefits of functional nucleic acids at different stages of cell-based therapy and discuss the feasibility of their practical clinical application. Finally, we offer insights into potential opportunities where chemists can significantly contribute to the innovative incorporation of functional nucleic acids to overcome challenges associated with this cutting-edge immunotherapy.