Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

Chhabra, Saurabh

doi:10.3390/ph10020040

Cited by 41 publications

(37 citation statements)

References 213 publications

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“…Thus, while bortezomib eliminates bortezomib-sensitive tumor plasma cell sub-clones, it also promotes the expansion of pre-existing bortezomib-resistant sub-clones, leading to relapse [14][15][16]. Consequently, the development of new therapeutic strategies, such as combination therapies, that overcome bortezomib resistance is urgently needed [17,18]. Proto-oncogene, serine/threonine kinase Bortezomib resistance may be mediated by the activation of the autophagy pathway, as an alternative mechanism of protein degradation [19,20].…”

Section: Introductionmentioning

confidence: 99%

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Lernia

Leone

Solimando

et al. 2020

JCM

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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.

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Section: Introductionmentioning

confidence: 99%

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Lernia

Leone

Solimando

et al. 2020

JCM

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“…Two challenges immediately become evident. Most urgent is the need to find alternatives for patients in whom these potent drug classes eventually fail 1,2,[9][10][11][12][13] . Second, is to understand the mechanisms of resistance and to seek methodologies, dosing strategies, and new drug combinations that can prevent or overcome relapse [14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

et al. 2020

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Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

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“…Furthermore, vorinostat and bortezomib inhibited tumor growth in a prostate tumor model in mice (43). Of note, there have been numerous clinical trials to improve the treatment of myeloma (and also lymphoma), in which bortezomib is approved as a drug, by combining HDAC inhibitors vorinostat or panobinostat with different proteasome inhibitors (25,44,45). Recently, the synergistic activity of HDAC inhibitor trichostatin (TSA) and bortezomib against taxan-resistant ovarian cancer cell lines has been reported (46).…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor effects of histone deacetylase inhibitor scriptaid and bortezomib against ovarian cancer cells

Janyst

Siernicka

et al. 2018

Oncol Rep

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Despite debulking surgery and good initial response to chemotherapy, the majority of patients with advanced ovarian cancer relapse and succumb to their disease. Thus, there is a pressing need to improve treatment outcome. In the present study, the antitumor activity of histone deacetylase (HDAC) inhibitor scriptaid in combination with bortezomib or conventional chemotherapeutics was tested in vitro against representative ovarian cancer cell lines: SKOV‑3, MDAH 2774, and OVP‑10. Incubation of ovarian cancer cells with scriptaid and bortezomib (or doxorubicin) led to synergistic antitumor effects. As shown in the Annexin V-FITC/PI assay and western blot analysis of caspase‑3/-9 and p21 protein expression, these synergistic antitumor effects were due to both induction of apoptosis and inhibition of proliferation. Since synergistic antitumor activity of scriptaid and bortezomib appeared in suboptimal concentrations, one can assume that the administration of the combination of these agents to ovarian cancer patients can exert the therapeutic effect in parallel with limited general toxicity of the treatment.

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Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

Cited by 41 publications

References 213 publications

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

Synergistic antitumor effects of histone deacetylase inhibitor scriptaid and bortezomib against ovarian cancer cells

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