Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells

Benvenuto, Monica; Ciuffa, Sara; Focaccetti, Chiara; Sbardella, Diego; Fazi, Sara; Scimeca, Manuel; Tundo, Grazia R.; Barillari, Giovanni; Segni, Maria; Bonanno, Elena; Manzari, Vittorio; Modesti, Andrea; Masuelli, Laura; Coletta, Massimo; Bei, Roberto

doi:10.1038/s41598-021-98450-6

Cited by 22 publications

(24 citation statements)

References 99 publications

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“…Therefore, it is reasonable to expect proteasome interaction with IDE to differ in relation to the cell line investigated and to the specific metabolic conditions (see Figure 5 B). Although the deepening of this aspect is outside the scope of this paper, it may be worth pointing out that CFZ administration turns out to decrease the immunodetection of proteasome particles by both anti-19S (e.g., Rpt5 subunit) and anti-20S (e.g., α7) antibodies (see Figure 5 B,D), a finding recently observed also for BTZ when administered to some human cell lines [ 50 ].…”

Section: Discussionsupporting

confidence: 56%

Insulin-Degrading Enzyme Is a Non Proteasomal Target of Carfilzomib and Affects the 20S Proteasome Inhibition by the Drug

et al. 2022

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Carfilzomib is a last generation proteasome inhibitor (PI) with proven clinical efficacy in the treatment of relapsed/refractory multiple myeloma. This drug is considered to be extremely specific in inhibiting the chymotrypsin-like activity of the 20S proteasome, encoded by the β5 subunit, overcoming some bortezomib limitations, the first PI approved for multiple myeloma therapy which is however burdened by a significant toxicity profile, due also to its off-target effects. Here, molecular approaches coupled with molecular docking studies have been used to unveil that the Insulin-Degrading Enzyme, a ubiquitous and highly conserved Zn2+ peptidase, often found to associate with proteasome in cell-based models, is targeted by carfilzomib in vitro. The drug behaves as a modulator of IDE activity, displaying an inhibitory effect over 10-fold lower than for the 20S. Notably, the interaction of IDE with the 20S enhances in vitro the inhibitory power of carfilzomib on proteasome, so that the IDE-20S complex is an even better target of carfilzomib than the 20S alone. Furthermore, IDE gene silencing after delivery of antisense oligonucleotides (siRNA) significantly reduced carfilzomib cytotoxicity in rMC1 cells, a validated model of Muller glia, suggesting that, in cells, the inhibitory activity of this drug on cell proliferation is somewhat linked to IDE and, possibly, also to its interaction with proteasome.

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Section: Discussionsupporting

confidence: 56%

Insulin-Degrading Enzyme Is a Non Proteasomal Target of Carfilzomib and Affects the 20S Proteasome Inhibition by the Drug

et al. 2022

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“…The proteasome is a large, multicatalytic protein complex that degrades many cellular proteins. Proteasome inhibitors (PIs) are an important new class of drugs for the treatment of multiple myelomas and mantle cell lymphomas, and they are currently in clinical trials for additional types of cancer ( 32 – 36 ). Oprozomib, an oral second-generation PI, increases the sensitivity of cervical cancer cells to apoptosis induced by CDDP ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…important new class of drugs for the treatment of multiple myelomas and mantle cell lymphomas, and they are currently in clinical trials for additional types of cancer (32)(33)(34)(35)(36). Oprozomib, an oral second-generation PI, increases the sensitivity of cervical cancer cells to apoptosis induced by CDDP (28).…”

Section: Discussionmentioning

confidence: 99%

Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo

Zhang

Zhang²,

Lin

et al. 2022

Front. Oncol.

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Proteasome inhibition is an attractive approach for anticancer therapy. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used as a standard chemotherapy drug in the treatment of solid malignant tumors, such as cervical cancer, ovarian cancer, colorectal cancer, and lung cancer. However, the development of CDDP resistance largely limits its clinical application. Proteasome inhibitors may enhance traditional chemotherapy agent-induced cytotoxicity and apoptosis. Marizomib (NPI-0052, salinosporamide A, Mzb), a second-generation proteasome inhibitor, shows synergistic anticancer activity with some drugs. Currently, the effect of Mzb on cervical cancer cell proliferation remains unclear. In this study, we explored the role of Mzb in three cervical cancer cell lines, HeLa, CaSki, and C33A, representing major molecular subtypes of cervical cancer and xenografts. We found that Mzb alone showed noteworthy cytotoxic effects, and its combination with CDDP resulted in more obvious cytotoxicity and apoptosis in cervical cancer cell lines and xenografts. In order to investigate the mechanism of this effect, we probed whether Mzb alone or in combination with CDDP had a better antitumor response by enhancing CDDP-induced angiopoietin 1 (Ang-1) expression and inhibiting the expression of TEK receptor tyrosine kinase (Tie-2) in the Ang-1/Tie-2 pathway, FMS-like tyrosine kinase 3 ligand (Flt-3L) and stem cell factor (SCF) as identified by a cytokine antibody chip test. The results suggest that Mzb has better antitumor effects on cervical cancer cells and can sensitize cervical cancer cells to CDDP treatment both in vitro and in vivo. Accordingly, we conclude that the combination of CDDP with Mzb produces synergistic anticancer activity and that Mzb may be a potential effective drug in combination therapy for cervical cancer patients.

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“…Equal loading and transfer of proteins was verified by Ponceau red staining of the membranes and by analyzing actin or tubulin expression. The assay was then performed as previously described, and signals were detected using enhanced chemiluminescence system ECL LiteAblot (Euroclone, Milan, Italy) [ 51 , 52 ].…”

Section: Methodsmentioning

confidence: 99%

Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

et al. 2022

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Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM.

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Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells

Cited by 22 publications

References 99 publications

Insulin-Degrading Enzyme Is a Non Proteasomal Target of Carfilzomib and Affects the 20S Proteasome Inhibition by the Drug

Insulin-Degrading Enzyme Is a Non Proteasomal Target of Carfilzomib and Affects the 20S Proteasome Inhibition by the Drug

Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo

Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

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