Review on Bortezomib Resistance in Multiple Myeloma and Potential Role of Emerging Technologies

Abstract

Multiple myeloma is a hematological cancer type. For its treatment, Bortezomib has been widely used. However, drug resistance to this effective chemotherapeutic has been developed for various reasons. 2D cell cultures and animal models have failed to understand the MM disease and Bortezomib resistance. It is therefore essential to utilize new technologies to reveal a complete molecular profile of the disease. In this review, we in-depth examined the possible molecular mechanisms that cause Bortezomib resistance and specifically addressed MM and Bortezomib resistance. Moreover, we also included the use of nanoparticles, 3D culture methods, microfluidics, and organ-on-chip devices in multiple myeloma. We also discussed whether the emerging technology offers the necessary tools to understand and prevent Bortezomib resistance in multiple myeloma. Despite the ongoing research activities on MM, the related studies cannot provide a complete summary of MM. Nanoparticle and 3D culturing have been frequently used to understand MM disease and Bortezomib resistance. However, the number of microfluidic devices for this application is insufficient. By combining siRNA/miRNA technologies with microfluidic devices, a complete molecular genetic profile of MM disease could be revealed. Microfluidic chips should be used clinically in personal therapy and point-of-care applications. At least with Bortezomib microneedles, it could be ensured that MM patients can go through the treatment process more painlessly. This way, MM can be switched to the curable cancer type list, and Bortezomib can be targeted for its treatment with fewer side effects.

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway

“…For instance, the proteasome inhibitor bortezomib (also known as Velcade, formerly PS-341) is a well-known Food and Drug Administration (FDA)-approved chemical anticancer drug widely used to treat patients with multiple myeloma and mantle cell lymphoma [ 31 ]. Although bortezomib has clearly shown an improvement in the 5-year survival rate in patients, many studies have claimed that the anticancer effects of bortezomib gradually decrease due to the upregulation of multidrug resistance (MDR), including pro-survival signaling pathways [ 32 , 33 ]. Mechanistically, upregulation of the expression of heat stress response (HSR)-related genes, such as heat shock protein family A (Hsp70) member 1B (HSPA1B), Hsp70 member 1A (HSPA1A), and DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1), in response to bortezomib was reported to decrease the proapoptotic effects of bortezomib in multiple myeloma cells [ 34 ].…”

Autophagy-related mechanisms for treatment of multiple myeloma

“…These platforms have the capability to generate results more rapidly than traditional clinical trials. Additionally, reconstructing disease models with 3D models and microfluidic systems can lead to the identification of new autophagy modulators [ 1 , 178 ] . Moreover, it is possible to conduct tests on new agents before administering them to the patient and to develop appropriate strategies that can be tailored according to the patient's needs.…”

“…Microfluidic systems are biomedical platforms that enable the controlled distribution of small amounts of liquids, which facilitates the simultaneous execution of multiple tests [ 179 ] . These devices allow for more accurate and quicker studies of the tumor microenvironment, metastasis, and drug resistance [ 1 ] . They also enable drug screening to be carried out rapidly and precisely, which assists in identifying new drug candidates with more efficiency [ 180 ] .…”

“…Multiple myeloma (MM) is associated with the proliferation of a single plasma B cell variant in the bone marrow and the secretion of monoclonal immunoglobulins [ 1 ] . MM is the second most common type of hematological malignancy worldwide, which accounts for approximately 10% of cases [ 2 ] .…”

Stability and potential degradation of the α′,β′-epoxyketone pharmacophore on ZnO nanocarriers: insights from reactive molecular dynamics and density functional theory calculations

“…This approach could be advantageous for drugs like CFZ, where the resistance is mediated by a protein (P-glycoprotein) that recognizes the structure of the drug and expels it from the cancer cell, preventing it from reaching its target site. 14,15 Therefore, it is essential to optimize their therapeutic efficacy to investigate the drug stability and potential degradation on different non-inert materials, like metal oxide nanocarriers (NCs). [16][17][18] When dealing with nanoparticle-based drug delivery, surfactants are very often mandatory to prevent coalescence and improve colloidal stability.…”