Management of Multiple Myeloma and Usage of Bortezomib: Perspective from India and Ukraine

Garg, Amit; Morgunskyy, Mykhaylo; Belagali, Yogesh; Gupta, Namita; Akku, Shyam; Choudhary, Deepak; Bhurani, Dinesh; Kryachok, Iryna; Korenkova, I.; Tsyapka, O.; Naithani, Rahul; Козлов, В. А.

doi:10.3389/fonc.2016.00243

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…Proteasomal inhibitors such as bortezomib, ixazomib, and carfilzomib are established chemotherapies used in multiple myeloma and mantle cell lymphoma patients with tolerable toxicity [ 8 , 9 ]. The efficacy of proteasomal inhibition is dependent on the sensitivity to the deregulation of protein-degradation systems as in the antibody-producing plasma cells.…”

Section: Introductionmentioning

confidence: 99%

Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

et al. 2021

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Incidence of hepatotoxicity following acute drug-induced proteasomal inhibition and development of chronic proteasome dysfunction in obesity and insulin resistance underscores the crucial importance of hepatic protein homeostasis albeit with an elusive molecular basis and therapeutic opportunities. Apart from lipotoxicity and endoplasmic reticulum (ER) stress, herein we report that hepatocytes are highly susceptible to proteasome-associated metabolic stress attune to altered redox homeostasis. Bortezomib-induced proteasomal inhibition caused severe hepatocellular injury independent of ER stress via proapoptotic Apoptosis Signal-regulating Kinase 1 (ASK1)- c-Jun N-terminal kinase (JNK1)- p38 signaling concomitant with inadequate peroxisome proliferator-activated receptor γ (PPARγ)- Nuclear factor erythroid 2-related factor 2 (Nrf2) -driven antioxidant response. Although inhibition of ASK1 rescued acute hepatotoxicity, hepatic depletion of PPARγ or its physiological activator pigment epithelium-derived factor (PEDF) further aggravated liver injury even under ASK1 inhibition, emphasizing that endogenous PPARγ driven antioxidant activity serves as a prerequisite for the favorable therapeutic outcome of ASK1 inhibition. Consequently, ASK1 inhibitor selonsertib and PPARγ agonist pioglitazone in pharmacological synergism ameliorated bortezomib-induced hepatotoxicity and significantly prolonged survival duration in mice. Moreover, we showed that proteasome dysfunction is associated with ASK1 activation and insufficient PPARγ/Nrf2-driven antioxidative response in a subset of human nonalcoholic steatohepatitis (NASH) patients and the preclinical NASH model. The latter remains highly responsive to the drug combination marked by revamped proteasomal activity and alleviated hallmarks of NASH such as steatosis, fibrosis, and hepatocellular death. We thus uncovered a pharmacologically amenable interdependent binodal molecular circuit underlying hepatic proteasomal dysfunction and associated oxidative injury.

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Section: Introductionmentioning

confidence: 99%

Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

et al. 2021

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“…Thus, the development of generic versions of medications, such as pomalidomide and carfilzomib, makes them more accessible and affordable for cancer patients. 80 Since 2017, generic pomalidomide has been available in India. The results are comparable to those reported in the literature for the original molecule.…”

Section: Treatment Of Patients With Rrmm In Indiamentioning

confidence: 99%

Management of Relapsed and Refractory Multiple Myeloma: Recent advances

Rathnam

Saju

Honey

2022

Indian J Med Paediatr Oncol

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Multiple myeloma (MM) accounts for ∼10% of total hematologic malignancies worldwide. In India, the incidence of MM has increased two-fold with marked heterogeneity. Significant improvements in terms of clinical outcomes have been observed in the management of MM in recent years. However, most patients develop a disease relapse with the first or subsequent treatments. A combination of immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (PIs; bortezomib) has been the mainstay for the therapeutic management of relapsed/refractory multiple myeloma (RRMM). This review highlights the management of RRMM with newer agents such as belantamab, carfilzomib, daratumumab, elotuzumab, ixazomib, mafadotin, selinexor, panobinostat, and venetoclax, with more focus on PIs. As a single agent and in combination with other drugs including dexamethasone and carfilzomib has been studied extensively and approved by the United States, European Union, and India. Clinical trials of these newer agents, either alone or in combination, for the treatment of RRMM in Western countries indicate survival, improved outcomes, and overall well-being. However, evidence in Indian patients is evolving from ongoing studies on carfilzomib and daratumumab, which will ascertain their efficacy and safety. Currently, several guidelines recommend carfilzomib-based, daratumumab-based, and panobinostat-based regimens in RRMM patients. Currently, with more accessible generic versions of these drugs, more Indian patients may attain survival benefits and improved quality of life.

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Management of Multiple Myeloma and Usage of Bortezomib: Perspective from India and Ukraine

Cited by 2 publications

References 19 publications

Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

Management of Relapsed and Refractory Multiple Myeloma: Recent advances

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