Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Pancheri, Elia; Guglielmi, Valeria; Wilczyński, Grzegorz M.; Malatesta, Manuela; Tonin, Paola; Tomelleri, Giuliano; Nowis, Dominika; Vattemi, Gaetano

doi:10.3390/cancers12092540

Cited by 44 publications

(45 citation statements)

References 159 publications

(252 reference statements)

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“…However, there are many notable issues in the drug development based on the post-translational modification of IκBα to be addressed for their future clinical usage. First, considering the unavoidable adverse effects of the IκBα-related NF-κB inhibitors (Pancheri et al, 2020), the pathophysiological mechanisms and the significance of the IκBα-NF-κB pathway in the development of diseases should be further clarified to provide the best ratio of benefit to risk. Second, the drug release controllability to ensure the controllable release rate under certain specific pathophysiological conditions should be taken into account because of the vast regulatory role of NF-κB pathway (Chen and Stark, 2019).…”

Section: Discussionmentioning

confidence: 99%

Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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The nuclear factor-kappa B (NF-κB) signaling pathway regulates a variety of biological functions in the body, and its abnormal activation contributes to the pathogenesis of many diseases, such as cardiovascular and respiratory diseases and cancers. Therefore, to ensure physiological homeostasis of body systems, this pathway is strictly regulated by IκBα transcription, IκBα synthesis, and the IκBα-dependent nuclear transport of NF-κB. Particularly, the post-translational modifications of IκBα including phosphorylation, ubiquitination, SUMOylation, glutathionylation and hydroxylation are crucial in the abovementioned regulatory process. Because of the importance of the NF-κB pathway in maintaining body homeostasis, understanding the post-translational modifications of IκBα can not only provide deeper insights into the regulation of NF-κB pathway but also contribute to the development of new drug targets and biomarkers for the diseases.

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Section: Discussionmentioning

confidence: 99%

Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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“…BZ is known to induce substantial off-target activities and causes various side effects, such as peripheral neuropathy, myelosuppression, and cardiac and skeletal toxicities, leading to dose modulation or early discontinuation of the therapy [ 31 ]. However, BZ in combination with other drugs for chemosensitization and synergy, immunomodulators such as lenalidomide or thalidomide, and corticosteroids such as dexamethasone or prednisone is commonly used as a first-line agent for the treatment of MM patients [ 32 , 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

Carfilzomib in Combination with Bortezomib Enhances Apoptotic Cell Death in B16-F1 Melanoma Cells

Lee

Lim

et al. 2021

Biology

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Proteasome inhibitors, such as bortezomib (BZ) and carfilzomib (CFZ), have been suggested as treatments for various cancers. To utilize BZ and/or CFZ as effective therapeutics for treating melanoma, we studied their molecular mechanisms using B16-F1 melanoma cells. Flow cytometry of Annexin V-fluorescein isothiocyanate-labeled cells indicated apoptosis induction by treatment with BZ and CFZ. Apoptosis was evidenced by the activation of various caspases, including caspase 3, 8, 9, and 12. Treatment with BZ and CFZ induced endoplasmic reticulum (ER) stress, as indicated by an increase in eIF2α phosphorylation and the expression of ER stress-associated proteins, including GRP78, ATF6α, ATF4, XBP1, and CCAAT/enhancer-binding protein homologous protein. The effects of CFZ on ER stress and apoptosis were lower than that of BZ. Nevertheless, CFZ and BZ synergistically induced ER stress and apoptosis in B16-F1 cells. Furthermore, the combinational pharmacological interactions of BZ and CFZ against the growth of B16-F1 melanoma cells were assessed by calculating the combination index and dose-reduction index with the CompuSyn software. We found that the combination of CFZ and BZ at submaximal concentrations could obtain dose reduction by exerting synergistic inhibitory effects on cell growth. Moreover, this drug combination reduced tumor growth in C57BL/6 syngeneic mice. Taken together, these results suggest that CFZ in combination with BZ may be a beneficial and potential strategy for melanoma treatment.

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“…Bortezomib is a first-in-class proteasome inhibitor targeting the 26S proteasome, a multi-subunit complex of the ubiquitin-proteasome system [ 99 ]. Bortezomib interfere with the FANC signaling, so it may influence DSBR [ 100 ].…”

Section: Ssa In Cancer Clinicmentioning

confidence: 99%

Single-Strand Annealing in Cancer

Błasiak

2021

IJMS

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DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.

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Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Cited by 44 publications

References 159 publications

Post-translational Modifications of IκBα: The State of the Art

Post-translational Modifications of IκBα: The State of the Art

Carfilzomib in Combination with Bortezomib Enhances Apoptotic Cell Death in B16-F1 Melanoma Cells

Single-Strand Annealing in Cancer

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