Heme Oxygenase Inhibition Sensitizes Neuroblastoma Cells to Carfilzomib

Abstract

Neuroblastoma (NB) is an embryonic malignancy affecting the physiological development of adrenal medulla and paravertebral sympathetic ganglia in early infancy. Proteasome inhibitors (PIs) (i.e., carfilzomib (CFZ)) may represent a possible pharmacological treatment for solid tumors including NB. In the present study, we tested the effect of a novel non-competitive inhibitor of heme oxygenase-1 (HO-1), LS1/71, as a possible adjuvant therapy for the efficacy of CFZ in neuroblastoma cells. Our results showed that CFZ increased both HO-1 gene expression (about 18-fold) and HO activity (about 8-fold), following activation of the ER stress pathway. The involvement of HO-1 in CFZ-mediated cytotoxicity was further confirmed by the protective effect of pharmacological induction of HO-1, significantly attenuating cytotoxicity. In addition, HO-1 selective inhibition by a specific siRNA increased the cytotoxic effect following CFZ treatment in NB whereas SnMP, a competitive pharmacological inhibitor of HO, showed no changes in cytotoxicity. Our data suggest that treatment with CFZ produces ER stress in NB without activation of CHOP-mediated apoptosis, whereas co-treatment with CFZ and LS1/71 led to apoptosis activation and CHOP expression induction. In conclusion, our study showed that treatment with the non-competitive inhibitor of HO-1, LS1 / 71, increased cytotoxicity mediated by CFZ, triggering apoptosis following ER stress activation. These results suggest that PIs may represent a possible pharmacological treatment for solid tumors and that HO-1 inhibition may represent a possible strategy to overcome chemoresistance and increase the efficacy of chemotherapic regimens.

Heme Oxygenase-1 Inhibition Sensitizes Human Prostate Cancer Cells towards Glucose Deprivation and Metformin-Mediated Cell Death

“…In this study, we evaluated MET-induced apoptosis in prostate cancer cells, using Annexin cytometry analysis. As shown in Figure 4, MET induced apoptosis in prostate cancer cells and, consistently with previous published results [17,84], HO-1 activity inhibition was able to further increase the cytotoxic effect induced by metformin in DU145 cells, indicating a synergistic effect between the two drugs.…”

“…Our previous studies showed that the chemotherapeutic drugs, carfilzomib and bortezomib, both increased HO-1 protein and gene expression via the activation of the UPR response, triggered by ER stress [17,70]. As shown in Figure 3, although glucose deprivation already increased HO-1 levels, MET significantly further induced HO-1, CHOP, and BAX mRNA levels, suggesting metformin can induce ER stress and cell apoptosis.…”

“…High levels of HO-1 have been frequently reported in different human cancers [14,15,16], playing a major role in drug resistance and regulation of cancer cell redox homeostasis [17,18,19,20,21,22].…”

Role of 17β-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells

“…Our results are consistent with these observations and showed that E2 resulted in a significant increase in the expression of genes involved in mitochondrial metabolism, biogenesis, and dynamics. Furthermore, our results showed that E2 resulted in a significant increase of HO-1, which is associated with increased chemoresistance and proliferative phenotype [47,48] (Figures 4(a)-4(c)). Consistently, E2 treatment increases FIS1 gene expression following 3 hours of treatment (Figure 4(d)).…”

α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells

“…3A,B) emerged as the most important network (Network 1). In particular, Gadd153/Chop (Ddit3), which the highest expression was observed between 24 and 48 hours (Table I, Supplementary data), was found associated to the casual network together with three regulators connected to each other: Trib3 37,38 , Alpha Serine/Threonine Kinase (Akt) 37,38 , Heme Oxygenase 1 (Hmox1) 39 (Fig. 3A,B).…”