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.
Highlights
Multiple myeloma (MM, see Table 1 for a list of abbreviations and acronyms used) is a malignant proliferation of monoclonal plasma cells (PCs) with a strong tropism for bone and bone marrow
light chain 3 beta (LC3B)-II is associated with both the outer and inner membranes of the autophagosome and is used as a marker for these organelles [39]. p62 is a cytoplasmic protein that shuttles ubiquitinated proteins to autophagosomes. It is integrated into autophagosomes through direct binding to LC3B-II and is efficiently degraded by autophagy [40]; total cellular expression levels of p62 inversely correlate with autophagic activity [39]
The introduction of bortezomib as a therapeutic strategy has improved the overall survival of MM patients, from less than 3 years in the 1990s to the current rate of roughly 10 years for patients under 65 and 5–6 years for older patients [42], 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment and die within 2 years after the diagnosis [42,43]
Summary
Multiple myeloma (MM, see Table 1 for a list of abbreviations and acronyms used) is a malignant proliferation of monoclonal plasma cells (PCs) with a strong tropism for bone and bone marrow. It is preceded by a preneoplastic phase, termed monoclonal gammopathy of undetermined significance (MGUS) [1]. The majority of patients respond to initial therapy, most will suffer disease relapse due to the proliferation of resistant tumor cells [3,4]. The development of new therapeutic strategies, such as combination therapies, that overcome bortezomib resistance is urgently needed [17,18]
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