Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma

Abstract

Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs’ efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.

Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia

“…Moreover, resistance to tumor treatment is still a critical problem, causing relapse and decreased overall survival. Several mechanisms that promote chemoresistance have been reported [92,93], and it is recognized that aggressive aptitudes and chemoresistance are correlated to the augmented communication function in tumor cells, and TNTs could have an effect in the onset of chemoresistance. Mitochondrial transfer may induce chemoresistance through different systems, comprising the inhibition of programmed cell death, the decreased production of ROS, and the increased salvaging of cells with altered mitochondria [94].…”

Metabolic Disorders in Multiple Myeloma

“…Therefore, alterations in glutamine metabolism might be involved both in treatment efficacy and drug resistance [ 38 ]. Glutaminase inhibitors may restore the efficacy of proteasome inhibitors by restoring caspase-mediated death signals [ 39 ]. c-Myc increases glutamine transporters and glutaminase (GLS) expression leading to enhanced glutaminolysis [ 40 ].…”

“…Therefore, myeloma cells acquire resistance to chemotherapeutic drugs. Interestingly, anti-mitochondrial agents have shown to restore the sensitivity of myeloma cells to proteasome inhibitors [ 39 ]. The combination of metabolic regulators with proteasome inhibitors may induce synthetic lethality, prevent the activation of resistance mechanisms and increase efficacy [ 141 , 149 ].…”

Modulating the Ubiquitin–Proteasome System: A Therapeutic Strategy for Autoimmune Diseases

“…Although the UPS participates in the pathogenesis of MS, details of the relationship between UPS and MS remain unknown [ 67 ]. Increased functional repression of the UPS and of interferon beta-1b (IFN-β1b) levels results in the development of MS. A better understanding of the molecular network of the UPS should provide more insight into the pathogenesis of MS. Myeloid leukemia 1 (MCL-1) is regulated by the UPS and is upregulated in MS [ 68 ].…”