Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies

Chowdhury, Sarwat; Sripathy, Smitha; Webster, Alyssa A.; Park, Angela; Lao, Uyen; Hsu, Joanne H.; Loe, Taylor K.; Bedalov, Antonio; Simon, Julian A.

doi:10.3390/molecules25030455

Cited by 25 publications

(18 citation statements)

References 49 publications

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“…Cambinol (CAM), a cell-permeable β-naphtol derivative, inhibits SIRT1 and SIRT2 activity (IC 50 = 56 uM and IC 50 = 59 uM, respectively) [20,21]. The mechanism of CAM action based on SIRT1 and SIRT2 inhibition leads to an increase of p53, FOXO3a, and Ku70 acetylation under stress condition; as a consequence, the cells become more sensitive to etoposide and paclitaxel, drugs commonly used in chemotherapy [22].…”

Section: Introductionmentioning

confidence: 99%

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin—An Isobolographic Analysis in Breast Cancer In Vitro Models

Hałasa

Łuszczki

Dmoszyńska‐Graniczka

et al. 2021

IJMS

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Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing.

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Section: Introductionmentioning

confidence: 99%

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin—An Isobolographic Analysis in Breast Cancer In Vitro Models

Hałasa

Łuszczki

Dmoszyńska‐Graniczka

et al. 2021

IJMS

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“…Therefore, DLBCL cells may also require NAD + for their proliferation. NAD + -dependent enzymes, such as GAPDH and the sirtuin family of ADP-ribosyltransferases, have been reported to be involved in the proliferation of DLBCL cells ( 44 , 45 ). One pathway for NAD + synthesis is the KYN pathway, of which KMO is the rate-limiting enzyme ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Viability of diffuse large B-cell lymphoma cells is regulated by kynurenine 3-monooxygenase activity

et al. 2021

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Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy that is the most common type of lymphoma in Japan. Previous studies have demonstrated that patients with DLBCL have a poor prognosis due to increased levels of indoleamine 2,3-dioxygnase and kynurenine (KYN). However, the roles of metabolites acting downstream of KYN and associated enzymes are not fully understood. The present study investigated the role of kynurenine 3-monooxygenase (KMO), which catalyzes the conversion of KYN to 3-hydroxykynurenine (3-HK), using serum samples from patients with DLBCL and human DLBCL cell lines with different KMO expression [STR-428 cells with high levels of KMO expression (KMO high ) and KML-1 cells with low levels of KMO expression (KMO low )]. Serum samples from 28 patients with DLBCL and 34 healthy volunteers were used to investigate the association between prognosis and KMO activity or 3-HK levels. Furthermore, to investigate the roles of KMO and its related metabolites, STR-428 and KML-1 cell lines, and the lymph nodes of patients with DLBCL were analyzed by reverse transcription-quantitative PCR for KMO, KYNU, 3-hydroxyanthranilate-3,4-dioxygenase and quinolinate phosphoribosyltransferase, by western blotting, and immunohistochemical or immunofluorescence staining for KMO, and by cell viability and NAD + /NADH assays. KYN pathway metabolites in serum samples were measured by HPLC. Serum 3-HK levels were regulated independently of serum KYN levels, and increased serum 3-HK levels and KMO activity were found to be associated with worse disease progression. Notably, the addition of KMO inhibitors and 3-HK negatively and positively regulated the viability of DLBCL cells, respectively. Furthermore, NAD + levels in KMO high STR-428 cells were significantly higher than those in KMO low KML-1 cells. These results suggested that 3-HK generated by KMO activity may be involved in the regulation of DLBCL cell viability via NAD + synthesis.

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“…Additionally, a ~260 amino acid catalytic domain in SIRTs is conserved across prokaryotes and eukaryotes, poses a major challenge in synthesizing isoform-selective SIRT inhibitors (34). Nevertheless, recent advancements in medicinal chemistry with some support from insights into structural features (163,164) have pushed the development of dual SIRT1/SIRT2, and SIRT3 selective inhibitors (165). A ~20 residue "C-terminal regulatory" (CTR) in SIRT1 was shown to form a β-hairpin with extended β-sheet of the catalytic domain, which can be an effective target to potentiate selectivity towards SIRT1 (75).…”

Section: Class III Selective Hdacimentioning

confidence: 99%

Rational Design and Development of HDAC Inhibitors for Breast Cancer Treatment

Mody

Bouckaert

Savvides

et al. 2021

CPD

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Background: Breast cancer is the most prevalent cancer amongst females across the globe and with over 2 million new cases reported in 2018, it poses huge economic burden to the already dwindling public health. A dearth of therapies in the pipeline to treat triple-negative breast cancers, and acquisition of resistance against existing line of treatments urges the need to strategize novel therapeutics in order to add new drugs to the pipeline. HDAC inhibitors (HDACi) is one such class of small molecule inhibitors that target histone deacetylases to bring about chromosomal remodelling and normalize dysregulated gene expression that marks breast cancer progression. Objective: While four HDACi have been approved by the FDA for treatment of different cancer types, no HDACi is specifically earmarked for clinical management of breast cancer. Owing to the differential HDAC expression pertaining to different types of breast cancers, isoform-selective HDAC inhibitors need to be discovered. Conclusion: This review attempts to set the stage for rational structure-based discovery of isoform-selective HDACi by providing structural insights into different HDACs and their catalytic folds based on their classes and individual landscape. Development of inhibitors in accordance with the differential expression of HDAC isoforms exhibited in breast cancer cells is a promising strategy to rationally design selective and effective inhibitors, adopting a ‘personalized-medicine’ approach.

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Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies

Cited by 25 publications

References 49 publications

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin—An Isobolographic Analysis in Breast Cancer In Vitro Models

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin—An Isobolographic Analysis in Breast Cancer In Vitro Models

Viability of diffuse large B-cell lymphoma cells is regulated by kynurenine 3-monooxygenase activity

Rational Design and Development of HDAC Inhibitors for Breast Cancer Treatment

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