Restoring microenvironmental redox and pH homeostasis inhibits neoplastic cell growth and migration: therapeutic efficacy of esomeprazole plus sulfasalazine on 3-MCA-induced sarcoma

Abstract

Neoplastic cells live in a stressful context and survive thanks to their ability to overcome stress. Thus, tumor cell responses to stress are potential therapeutic targets. We selected two such responses in melanoma and sarcoma cells: the xc- antioxidant system, that opposes oxidative stress, and surface v-ATPases that counteract the low pHi by extruding protons, and targeted them with the xc- blocker sulfasalazine and the proton pump inhibitor esomeprazole. Sulfasalazine inhibited the cystine/cysteine redox cycle and esomeprazole decreased pHi while increasing pHe in tumor cell lines. Although the single treatment with either drug slightly inhibited cell proliferation and motility, the association of sulfasalazine and esomeprazole powerfully decreased sarcoma and melanoma growth and migration. In the 3-methylcholanthrene (3-MCA)-induced sarcoma model, the combined therapy strongly reduced the tumor burden and increased the survival time: notably, 22 % of double-treated mice recovered and survived off therapy. Tumor-associated macrophages (TAM) displaying M2 markers, that abundantly infiltrate sarcoma and melanoma, overexpress xc- and membrane v-ATPases and were drastically decreased in tumors from mice undergone the combined therapy. Thus, the double targeting of tumor cells and macrophages by sulfasalazine and esomeprazole has a double therapeutic effect, as decreasing TAM infiltration deprives tumor cells of a crucial allied. Sulfasalazine and esomeprazole may therefore display unexpected therapeutic values, especially in case of hard-to-treat cancers.

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

“…Moreover, similar effects were obtained in CSCs co-treated with either Etoposide and SSZ (Figure 2a Together these results demonstrate that ER-CSCs maintain their resistance to Etoposide and show that ER-CSC generation is totally inhibited by co-treatments with SSZ or C2-4. Moreover, the data obtained confirm that the inhibition of xCT is a useful strategy for enhancing the effect of chemotherapy [37][38][39][40][41][42] and, although the use of SSZ is limited due to its low bioavailability, its employment has been recently considered to treat high In contrast, the same treatments did not induce any significant alteration in the formation/propagation of ER-CSCs until two weeks of exposure (Figure 2b). In fact, Etoposide treatment reduced CSC propagation by 38% at four weeks, and this effect remained unchanged until six weeks of treatment (Figure 2b).…”

“…Together these results demonstrate that ER-CSCs maintain their resistance to Etoposide and show that ER-CSC generation is totally inhibited by co-treatments with SSZ or C2-4. Moreover, the data obtained confirm that the inhibition of xCT is a useful strategy for enhancing the effect of chemotherapy [ 37 , 38 , 39 , 40 , 41 , 42 ] and, although the use of SSZ is limited due to its low bioavailability, its employment has been recently considered to treat high risk NB [ 43 ]. In addition, the results obtained in C2-4-co-treated cells suggest that the inhibition of PKCα could be a novel way to sensitize CSCs to therapy by sustaining GSH depletion.…”

A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors

“…In our model Nlrp3 N475K/1 mouse inflammatory cells displayed features including hyperresponsiveness to LPS, high and fast secretion of IL-1b independent of ATP stimulation, and low IL-1Ra levels, which are hallmarks of monocytes from patients with CAPS. [7][8][9]27 Our Nlrp3 N475K/1 mice exhibited a milder phenotype and longer survival compared with Nlrp3 KI mice generated in previous studies, 10,11 allowing us to study the long-term consequences of chronic persistent inflammation. Moreover, unlike the other CAPS mouse models, Nlrp3 N475K/1 mice had amyloid deposits in various tissues and high levels of serum amyloid A protein.…”

“…25,26 Surface v-ATPases allow externalization of H 1 generated in excess intracellularly, thus maintaining a neutral intracellular pH. By blocking surface v-ATPases, PPIs block H 1 extrusion and decrease the vitality of tumor cells 27 and proinflammatory cytokine production by activated macrophages. 23 Remarkably, treatment with PPIs protects mice from sepsis by decreasing both TNF-a and IL-1b production and inhibits IL-1b secretion by monocytes from healthy subjects and patients with CAPS ex vivo.…”

Effect of starvation on brain glucose metabolism and 18F-2-fluoro-2-deoxyglucose uptake: an experimental in-vivo and ex-vivo study

“…Gluthatione reductase activity was evaluated spectrophotometrically, at 405 nm, using Glutathione Reductase Assay Kit (Abcam: ab83461) following the manufacturer’s instructions. Real-time PCR evaluation was performed according to the standard procedures of our lab [ 22 ].…”