Synergistic Combination of Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid and Natural Flavonoid Curcumin Exhibits Anticancer and Antibacterial Activity

2020 ◽  
Vol 20 ◽  
Author(s):  
Ergül M. Altundağ ◽  
Kübra Toprak ◽  
Gizem Şanlıtürk ◽  
Mümtaz Güran ◽  
Cahit Özbilenler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Cancer ◽  
Mtt Assay ◽  
Combination Treatment ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid ◽  
Synergistic Activity ◽  
Combination Strategy ◽  
P27 Kip1

Background and Objective: Curcumin is an effective anti-cancer agent used in thyroid cancer treatments. However, its use in clinical applications is limited due to low solubility and bioavailability. In this study, a novel combination strategy was applied by combining curcumin with suberoylanilide hydroxamic acid (SAHA) to increase both bioavailability of curcumin and the efficiency of SAHA, which has limited efficiency when used alone. Methods: MTT assay was used to determine the cell viability of B-CPAP cells upon treatment with SAHA, curcumin and their combinations. Synergistic interactions between two agents were analyzed by Calcusyn software. Apoptosis and cell cycle assays were measured by flow cytometry. Expressions of apoptotic and cell cycle-related proteins (PARP, P21/CDKN1A/WAF1, P27/KIP1) were examined by western blot analysis. Broth microdilution assay was performed to determine minimum inhibitory concentration (MIC) values against S.aureus. Results: Based on MTT assay, IC50 values for SAHA and curcumin were determined as 0.91 μM and 20.97 μM, respectively. The combination index CI value was determined as 0.891 in B-CPAP cells, which demonstrate synergistic activity. The apoptotic effect was achieved by combination treatment (51.85%) on B-CPAP cells by using half of the dose required for SAHA and curcumin alone. Combination treatment showed significant increase in percentage of B-CPAP cells in S-phase due to the cell arrest. Cleaved-PARP, P21/CDKN1A/WAF1 and P27/KIP1 protein expressions were upregulated. Curcumin was found to have better antimicrobial activity than SAHA as having a lower MIC value and checkerboard synergy analysis revealed that, the two compounds co-operate synergistically for the in-vitro killing of S. aureus. Conclusion: In the present study, synergistic combinations of SAHA and curcumin were shown to have both anticancer and antibacterial activities that would provide a novel thyroid cancer treatment strategy.

Antitumor Activity of Suberoylanilide Hydroxamic Acid against Thyroid Cancer Cell Lines In vitro and In vivo

2006 ◽  
Vol 12 (18) ◽  
pp. 5570-5577 ◽  
Author(s):  
Quang T. Luong ◽  
James O'Kelly ◽  
Glenn D. Braunstein ◽  
Jerome M. Hershman ◽  
H. Phillip Koeffler
Keyword(s):  
Thyroid Cancer ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines

scholarly journals CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5782
Author(s):  
Ashwini Makhale ◽  
Devathri Nanayakkara ◽  
Prahlad Raninga ◽  
Kum Kum Khanna ◽  
Murugan Kalimutho
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Triple Negative ◽  
Annexin V ◽  
Replication Stress ◽  
Breast Cancer Cell Lines ◽  
Combination Strategy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

scholarly journals Suberoylanilide hydroxamic acid during in vitro culture improves development of dog-pig interspecies cloned embryos but not dog cloned embryos

2018 ◽  
Vol 64 (3) ◽  
pp. 277-282 ◽  
Author(s):  
Min Jung KIM ◽  
Hyun Ju OH ◽  
Yoo Bin CHOI ◽  
Sanghoon LEE ◽  
Erif Maha Nugraha SETYAWAN ◽  
...  
Keyword(s):  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid

scholarly journals Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis

2012 ◽  
Vol 36 (3) ◽  
pp. 342-349 ◽  
Author(s):  
Chong Zhang ◽  
Yong-Ku Ryu ◽  
Taylor Z. Chen ◽  
Connor P. Hall ◽  
Daniel R. Webster ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Synergistic Activity ◽  
Cycle Arrest

Synergistic Preclinical Activity of Bortezomib with Suberoylanilide Hydroxamic Acid (SAHA) in Primary Effusion Lymphoma (PEL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1650-1650
Author(s):  
Shruti Bhatt ◽  
Brittany Ashlock ◽  
Ngoc Toomey ◽  
Enrique Mesri ◽  
Juan Carlos Ramos ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Hdac Inhibitor ◽  
Hydroxamic Acid ◽  
Primary Effusion Lymphoma ◽  
Suberoylanilide Hydroxamic Acid ◽  
Lytic Gene ◽  
Lytic Reactivation ◽  
Apoptotic Genes

Abstract Abstract 1650 Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma typically presenting as effusions in the serous body cavities without a contiguous tumor mass. PEL may develop in elderly immunosuppressed HIV-negative individuals but more commonly affects HIV-positive patients, accounting for 4% of all lymphomas in this population. Kaposi's sarcoma-associated herpesvirus (KSHV) is directly implicated in the pathogenesis of PEL, however in most patients the malignant B cells are also coinfected with Epstein-Barr virus which may facilitate transformation. Current chemotherapeutic approaches result in dismal outcome of PEL patients with a median survival of only 6 months. Consequently, development of new therapeutic approaches is urgently needed. Recently we reported development of the UM-PEL1 direct xenograft mice model reproducing human PEL (Sarosiek, PNAS 2010) in which bortezomib (BORT) induced virus lytic reactivation leading to malignant B cell death and transient remission of the PEL in vivo. Further improvement on this monotherapy is warranted. Recent studies have shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor is a highly effective viral lytic-cycle inducer. As herpesviruses are dependent on the proteasome for replication and mature viral production, induction of lytic replication with concomitant inhibition of the proteasome may provide a highly targeted strategy for eradicating KSHV infected cells without leading to increased viremia. Consequently, we hypothesized that combining BORT with SAHA may act synergistically in PEL tumors. Incubation of human PEL cell lines, UM-PEL1, BC1, BC3 and BC5 with BORT-SAHA resulted in increased apoptotis compared to individual treatment with BORT or SAHA, as assayed by flow cytometry using YO-PRO/PI staining. Concordantly, a statistically significant decrease in UM-PEL1 cell proliferation and viability, as examined by an MTT assay, was observed at 48 and 72 hours following combination therapy as compared to untreated cells or cells treated individually with BORT or SAHA. Cell cycle analysis demonstrated that BORT-SAHA combination induced more pronounced G1 cell cycle arrest and apoptosis as compared to individual treatments. SAHA induced a more robust KSHV lytic reactivation compared to BORT. Intriguingly, the BORT-SAHA combination led to an increased expression of the master lytic transactivator RTA and thymidine kinase, however the late lytic gene, K8.1, showed reduced mRNA expression relative to the individual SAHA treatment. These findings were further confirmed by immunofluorescence staining of the K8.1 protein suggesting that BORT could inhibit mature virion production in lytically reactivated malignant B-cells. To comprehensively examine the activity of the BORT-SAHA combination compared to individual BORT or SAHA treatments in vivo, we used UM-PEL1 direct xenograft model. Mice receiving intraperitoneal BORT-SAHA combination showed statistically significant prolonged survival compared to all the control treatments (p<0.001). Since PEL cells are known to be highly dependent on NF-κB for survival, we examined whether the apoptosis induced by the combination treatment was due to the inhibition of this pro-survival pathway. In contrast to our previous observations that individual BORT treatment did not alter NF-κB activity, the in vivo addition of SAHA led to NF-κB inhibition as demonstrated by gel shift assay. Moreover, Western blotting demonstrated downregulation of anti-apoptotic genes, upregulation of pro-apoptotic genes along with the rise in the p53, p21 and increased acetylation of histone 3 in the combination treated mice versus BORT alone. Further, RTA and early lytic gene expression confirmed our in vitro findings that KSHV lytic reactivation is enhanced in the BORT-SAHA treated mice compared to individual treatments. However, transcription of all late lytic genes tested (gB, K8.1, gM, ORF38, ORF67, ORF68) was uniformly inhibited in the animals treated with the BORT-SAHA as compared to SAHA alone, suggesting that the virus was unable to complete the full replicative cycle. In conclusion, this study demonstrates strong pre-clinical activity of the combination of proteasome inhibitor with HDAC inhibitor as a potent anti-PEL therapy that triggers apoptosis by prompting KSHV lytic reactivation without increasing infectious virus production. Disclosures: No relevant conflicts of interest to declare.

Modulation of the anti-tumor activity of VEGF blockade by metformin.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23009-e23009
Author(s):  
Mohamed Selmy ◽  
Elisabetta Zulato ◽  
Anna Pasto ◽  
Stefano Indraccolo
Keyword(s):  
Cell Cycle ◽  
Tumor Growth ◽  
Glucose Deprivation ◽  
Potential Candidate ◽  
Ampk Activation ◽  
Proliferative Capacity ◽  
Combination Strategy ◽  
Mtor Inhibition

e23009 Background: The payoff from first-generation angiogenesis inhibitors was commonly temporary, due to the development of intrinsic as well as acquired resistance. Apart from the vascular resistance due to circumventing VEGF blockade by proangiogenic factors, resistance has also been associated with assortment of resistant clones. Accordingly, a combination strategy was proposed to overcome such resistance. Metformin, as a potential candidate, has received considerable concern as an anticancer agent. Methods: IN-VITRO WORK;Cells were divided into normoxic and hypoxic groups. For both, four subgroups were developed; control, metformin, glucose deprivation and a subgroup in which cells were subjected to both glucose deprivation and metformin treatment. Cells were then subjected to analysis for Apoptosis, Cell cycle progression and western blot. IN-VIVO WORK; Tumor growth was assessed IGROV-1 subcutaneous xenografts. Animal were divided into four groups; control, Metformin, Bevacizumab and a fourth group receiving both drugs. Tumor growth was assessed along treatments and at time of sacrifice.After sacrificing animals, tumors were further analyzed for; necrosis, apoptosis, proliferative capacity, activation of AMPK and its downstream effectors. Results: Our in-vitro results suggested an anti-proliferative effect of metformin in terms of apoptosis, cell cycle arrest, AMPK activation and mTOR inhibition at various time points. In-vivo experiments revealed a significant decrease of tumor weight and proliferative capacity in tumors treated with both drugs and a trend toward a decrease in tumor growth along the treatment. Yet, there was no difference between the bevacizumab and the combination groups regarding AMPK activation suggesting another mechanism to exert the combination effect. The effect of Metformin on CSC percentage and viability was tested. Glucose deprivation plus hypoxia lead to increase in CSC population, while adding metformin to bevacizumab reverse this augmentation in CSC numbers. Conclusions: Study represents a proof of concept study demonstrating a positive modulatory effect of metformin addition to bevacizumab. Additional experimental work on a wider scale is running to ascertain the current results.

scholarly journals Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

2021 ◽  
Vol 14 (11) ◽  
pp. 1177
Author(s):  
Tarek S. Ibrahim ◽  
Azizah M. Malebari ◽  
Mamdouh F. A. Mohamed
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Hydroxamic Acid ◽  
Phenyl Group ◽  
Cancer Cell Lines ◽  
Anticancer Activities ◽  
Molecular Docking Study

Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. Therefore, in this work, based on introducing 3,4,5-trimethoxy phenyl group as a part of the CAP moiety, in addition to incorporating 4–6 aliphatic carbons linker and using COOH or hydroxamic acid as ZBG, 12 novel EGFR/HDAC hybrid inhibitors 2a–c, 3a–c, 4a–c and 5a–c were designed, constructed, and evaluated for their anticancer activities against 4 cancer cell lines (HepG2, MCF-7, HCT116 and A549). Among all, hybrids with hydroxamic acid 4a–c and 5a, exhibited the highest inhibition against all cancer cell lines with IC50 ranging from 0.536 to 4.892 μM compared to Vorinostat (SAHA) with IC50 ranging from 2.43 to 3.63 μM and Gefitinib with IC50 ranging from 1.439 to 3.366 μM. Mechanistically, the most potent hybrids 4a–c and 5a were further tested for their EGFR and HDACs inhibitory activities. The findings disclosed that hybrid 4b displayed IC50 = 0.063 µM on the target EGFR enzyme which is slightly less potent than the standard Staurosporine (IC50 = 0.044 µM). Furthermore, hybrid 4b showed less HDAC inhibitory activity IC50 against HDAC1 (0.148), 2 (0.168), 4 (5.852), 6 (0.06) and 8 (2.257) than SAHA. In addition, the investigation of apoptotic action of the most potent hybrid 4b showed a significant increase in Bax level up to 3.75-folds, with down-regulation in Bcl2 to 0.42-fold, compared to the control. Furthermore, hybrid 4b displayed an increase in the levels of Caspases 3 and 8 by 5.1 and 3.15 folds, respectively. Additionally, the cell cycle analysis of hybrid 4b revealed that it showed programmed cell death and cell cycle arrest at G1/S phase. Moreover, all these outcomes together with the molecular docking study recommended the rationalized target hybrids 4a–c and 5a, particularly 4b, may be considered to be promising lead candidates for discovery of novel anticancer agents via dual inhibition of both EGFR/HDAC enzymes.

JQ1, a Potent c-MYC Inhibitor Overcomes Rituximab-Chemotherapy Resistance in Lymphoma Pre-Clinical Models

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2761-2761
Author(s):  
Juan J Gu ◽  
Qunling Zhang ◽  
Cory Mavis ◽  
Myron S. Czuczman ◽  
Francisco J. Hernandez-Ilizaliturri
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Synergistic Activity ◽  
Targeted Agents ◽  
Chemotherapy Agents

Abstract Background: The poor clinical outcomes of patients with aggressive B-cell lymphoma in the post-rituximab era, stress the need to identify and/or optimize novel targeted agents. Several retrospective and prospective clinical studies had demonstrated that C-myc expression correlates with a poor clinical outcome in patients with newly diagnosed or relapsed/refractory diffuse large B-cell lymphoma (DLBCL). To this end, we evaluated the therapeutic effects of targeting C-myc using JQ1, a novel bromodomain inhibitor in rituximab-sensitive or -resistant models. Methods: A panel of rituximab-sensitive (RSCL) or rituximab-resistant (RSCL) cell lines was exposed to JQ1 (0-100 µM) for 24-72 hrs. Changes in cell viability and cell cycle distribution were evaluated using the Presto Blue assay and flow cytometry respectively. IC50 values were calculated using the GraphPad Prism6 software. Subsequently lymphoma cells were exposed to JQ1 or vehicle and various chemotherapy agents such as doxorubicin (0.5, 1, 2µM), dexamethasone (1µM), Ibrutinib (1µM), bortezomib (10-20nM) or carfilzomib (10nM) for 48 hours. Coefficient of synergy was calculated using the CalcuSyn software. Results: In vitro exposure of RRCL and to a lesser degree RSCL to JQ1 resulted in a dose- and time-dependent cell death. Strong synergistic activity was observed when JQ1 was combined with doxorubicin, dexamethasone bortezomib or carfilzomib in vitro. Cell cycle analysis demonstrated that in vitro of RSCL or RRCL to JQ1 resulted in G1 cell cycle arrest. Conclusions: In summary, our data suggests that targeting C-myc expression using JQ1 results in anti-tumor activity against RSCL and RRCL. In addition, JQ1 exhibited synergistic activity when combined with chemotherapy agents (doxorubicin or dexamethasone) or targeted agents (bortezomib or carfilzomib). On going studies are aimed to study the mechanisms by which c-myc inhibition results in cell death in RSCL and RRCL. JQ1 is a distinct targeted agent undergoing clinical evaluation in patients with relapsed/refractory lymphomas. Molecular studies dissecting the cellular pathways affected by JQ1 are important in order to further advance the clinical development of c-myc inhibitors in lymphoid malignancies. (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Fund) Disclosures Czuczman: Boehringer-Ingelheim: Other: Advisory Board; Immunogen: Other: Advisory board; MorphoSys: Consultancy; Celgene: Employment.

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