New strategies to overcome therapeutic resistance in glioblastoma

Glioblastoma (GBM) remains a significant medical challenge due to its resistance to conventional chemotherapy and radiotherapy, to great cellular heterogeneity, high regeneration rate, and pres- ence of cancer stem cells. Furthermore, the blood–brain barrier represents a physiological obstruction to the delivery of conven- tional chemotherapy, reducing the efficacy of treatments. Cathep- sins are lysosomal proteases involved in several physiological and pathological processes, and their key roles in modulating cell death and pharmacological resistance has recently been demon- strated. In particular, cathepsin B is a nodal regulatory protein in different types of cell death, such as apoptosis, pyroptosis, fer- roptosis, necroptosis, and autophagy. Actually, overexpression of cathepsins is among the causes of GBM angiogenesis and tumour progression. Novel Pt(IV)-based drugs, Pt(IV)Ac-POA and DB178, whose efficacy has already been demonstrated on the human astroglioma cell line U251 and on the human glioblas- toma cell line T98G, have shown improved anticancer efficacy, especially when conjugated with other compounds possessing synergistic effects. This work aims to assess the effects of these two drugs in cathepsin modulation on the U251 and T98G cell lines, and whether the inhibition of cathepsin B activity may be proven useful in brain cancer therapy. The immunocytochemical and biochemical results on the two cell lines highlight that both compounds maintained basal cathepsin B levels, while efficiently activating programmed cell death mechanisms, as investigated by optical and electronic microscopy. These data emphasize the effectiveness of the two platinum-based pro-drugs, which do not rouse cathepsin B in stimulating programmed cell death. For these reasons, the possible synergy with cathepsin B inhibitors could reveal noteworthy targets for novel therapeutic approaches