Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Abstract

Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

“…Here, KMS-20 cells presented a lower sensitivity to bortezomib and ixazomib than KMS-26 and KMS-28BM cells. Although proteasome β5 subunit overexpression and the induction of autophagy by a proteasome inhibitor have been associated with resistance in multiple myeloma (MM) cells [ 45 , 46 , 47 ], our results showed that there was no change in the expression level of the proteasome β5 subunit, inhibition level of proteasome β5 subunit activity, or degree of autophagy induction by bortezomib and ixazomib. These results suggest that a low sensitivity to bortezomib and ixazomib relies on other factors.…”

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

“…CQ and HCQ can enhance carfilzomib induced cell apoptosis by inhibition of autophagy toward MM (Jarauta et al, 2016;Baranowska et al, 2016). The cytotoxicity of bortezomib on MM also can be augmented by Baf1, HCQ, or macrolide antibiotics via inhibiting prosurvival autophagy in cotreatment manner (Di Lernia et al, 2020;Miyazawa, 2011;Moriya et al, 2013). Moreover, 3-MA promoted sensitivity of glioblastoma cells to bortezomib by inhibition of bortezomib induced cytoprotective autophagy .…”

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

“…Assessing oxygenation in the different layers of tumour pinpoint that there is a progressive increase of nutrient and oxygen levels across the inner depth [ 162 ], thus fueling genomic instability [ 163 ], the cancer progression (PD) [ 16 ], the switch to anaerobic metabolism [ 164 ], as well as the epithelial–mesenchymal transition, metastases [ 165 ], and the induction of cancer “stem cell” phenotype [ 166 ]. Hypoxia is a hallmark of cancer, inducing many abnormalities with prognostic consequences linked to defects in apoptosis and autophagy [ 167 , 168 ] and the resistance to radio-chemotherapy [ 169 , 170 , 171 ] and immunotherapy [ 13 , 172 , 173 ] likewise hamper the cancer aggressive phenotype acquisition, while shaping a pro-angiogenic, inflamed, and immunosuppressive neoplastic ecosystem [ 154 , 174 , 175 ]. Consequently, it is necessary either to target many different actors on the scene within the neoplastic niche or attempt to homogenize the cancer heterogeneity [ 161 ].…”