Discovery of class I histone deacetylase inhibitors based on romidpesin with promising selectivity for cancer cells

2020 ◽  
Vol 12 (4) ◽  
pp. 311-323
Author(s):  
Kuojun Zhang ◽  
Yiwu Yao ◽  
Zhengchao Tu ◽  
Chenzhong Liao ◽  
Zhen Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Agents ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
Selective Inhibition ◽  
Class I ◽  
Antitumor Effects ◽  
Synthesis Strategy

Aim: Class I histone deacetylases (HDACs) are considered to be promising anticancer targets, but selective inhibition of class I HDAC isoforms remains a challenge. Methods & results: Previously, we obtained a selective class I HDAC inhibitor 9 based on a macrocyclic HDAC inhibitor Romidpesin. As our continuous efforts, a library of novel cyclicdepsipeptides based on 9 was established using a convergent synthesis strategy. The most active compounds 10, 16 and 19 selectively inhibit class I HDACs and exhibit promising nanomolar antiproliferative activities against several cancer cell lines with excellent selectivity toward cancer cells over normal cells. Besides, compound 10 demonstrates excellent antitumor effects in human prostate carcinoma PC3 xenograft models with no observed toxicity. Conclusion: These cyclicdepsipeptides show great therapeutic potential as novel anticancer agents for clinical translation.

scholarly journals Discovery of Novel Class of Histone Deacetylase Inhibitors as Anticancer Agents

2021 ◽  
Author(s):  
Raafat El-Awady ◽  
Ekram Salah ◽  
Rifat Hamoudi ◽  
Ralph Mazitschek ◽  
Wafaa Ramadan ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cancer Cell Line ◽  
Selective Inhibition ◽  
Anticancer Activities ◽  
Biological Assays ◽  
Drug Candidates ◽  
New Compounds ◽  
Apoptotic Effects

Abstract Selective inhibition of histone deacetylases (HDACs) is a paramount strategy in the field of anticancer lead drug development. However, the lack of selectivity among these isozymes and the adverse side effects that arise from the inhibition of certain HDACs limits their clinical applications. Phenotypic screening of an in-house pilot library of about 70 small molecules against various HDAC isozymes led to the discovery of five compounds which displayed varying degrees of HDAC isozyme selectivity. The anticancer activities of these molecules were validated using various biological assays including transcriptomic studies. Compounds 15, 14, and 19 possessed selective inhibitory activity against HDAC5, while 28 displayed selective inhibition of HDAC1 and HDAC2. Compound 22 was found to be a selective inhibitor for HDAC3 and HDAC9. In the MCF7 breast cancer cell line the new compounds showed potent anti-proliferative activity, increased acetylation of histones and induced cells apoptosis. The new compounds’ apoptotic effects were validated through the upregulation of caspases3 and 7 and downregulation of C-MYC, BCL2, BCL3 and NFĸB genes. Furthermore, the new compounds arrested cell cycle at different phases, which was confirmed through downregulation of the CDK1, 2, 4, 6, E2F1 and RB1 proteins. Together our findings provide the foundation for the development of new chemical probes as potential lead drug candidates for the treatment of cancer.

scholarly journals ZEB 1‐associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat

2015 ◽  
Vol 7 (6) ◽  
pp. 831-847 ◽  
Author(s):  
Simone Meidhof ◽  
Simone Brabletz ◽  
Waltraut Lehmann ◽  
Bogdan‐Tiberius Preca ◽  
Kerstin Mock ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Hdac Inhibitor ◽  
Class I

scholarly journals Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

2015 ◽  
Vol 308 (11) ◽  
pp. H1391-H1401 ◽  
Author(s):  
Santhosh K. Mani ◽  
Christine B. Kern ◽  
Denise Kimbrough ◽  
Benjamin Addy ◽  
Harinath Kasiganesan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Left Ventricular ◽  
Class I ◽  
Matrix Metalloproteinase 2 ◽  
Lv Function ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Lv Remodeling

Left ventricular (LV) remodeling, after myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb- and class I-selective HDAC inhibitors on MMP-2 and MMP-9 abundance and determined if treatment resulted in the attenuation of adverse LV and extracellular matrix remodeling and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb HDAC inhibitor tichostatin A or suberanilohydroxamic acid (voronistat) compared with MI-only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either tichostatin A or suberanilohydroxamic acid treatment. Class I HDAC activity was dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI, similar to class I/IIb HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.

scholarly journals Sodium Selenite Accentuates the Therapeutic Effect of Adriamycin Prodrug (PADM) against Gastric Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Shengquan Tan ◽  
Jiapeng Mo ◽  
Zixiong Zhang ◽  
Chuying Huang ◽  
Yi Zou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Sodium Selenite ◽  
Therapeutic Potential ◽  
Mitochondrial Fission ◽  
Combined Treatment ◽  
Mitochondrial Morphology ◽  
Gastric Cancer Cells ◽  
Antitumor Effects ◽  
And Migration

Selenium has remained a controversial character in cancer research. While its antitumor effects have been widely demonstrated, further evidence is required to establish it as a robust treatment regime. Sodium selenite (SS), an inorganic selenium, reportedly affected the proliferation and redifferentiation of gastric cancer cells, but whether it could act as a complement to conventional chemotherapeutic drugs for combination therapy is uncertain. Herein, SGC-7901 and MGC-803 gastric cancer cells were treated with PADM (Ac-Phe-Lys-PABC-ADM), a prodrug of doxorubicin/adriamycin (ADM), and the combined antitumor effects of the two drugs were evaluated. Characterization after treatment revealed that although PADM exhibited antitumor effects individually by inhibiting the proliferation and migration of gastric cancer cells and inducing apoptosis, the addition of SS significantly amplified these effects. Furthermore, gastric cancer cell apoptosis triggered by the combined treatment of SS and PADM may involve the participation of mitochondrial apoptosis, as evidenced by the changes in mitochondrial morphology and occurrence of mitochondrial fission. Collectively, SS could be a strong complementary drug that accentuates the therapeutic potential of PADM in gastric cancer treatment and management, and its significance could contribute to unique and innovative anticancer strategies.

scholarly journals Histone Deacetylase Inhibitors Sensitize TRAIL-Induced Apoptosis in Colon Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 645 ◽  
Author(s):  
Baojie Zhang ◽  
Bin Liu ◽  
Deng Chen ◽  
Rita Setroikromo ◽  
Hidde J. Haisma ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Normal Mucosa ◽  
Class I ◽  
Colon Cancer Cells ◽  
Induced Apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi’s), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi’s, however, show considerable toxicity constraining clinical use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi’s. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi’s on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We observed that RGFP966 and PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models.

scholarly journals Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 113 ◽  
Author(s):  
Alaa A. A. Aljabali ◽  
Hamid A. Bakshi ◽  
Faruck L. Hakkim ◽  
Yusuf A. Haggag ◽  
Khalid M. Al-Batanyeh ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
In Vitro Cytotoxicity ◽  
Colon Cancer Cells ◽  
Chemical Colitis ◽  
Clinical Trails

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC–BSA nanoparticles (NPs). These PIC–BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC–BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC–BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC–BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC–BSA NPs, enhances its therapeutic potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possible human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients.

scholarly journals MDA-MB-231 Breast Cancer Cells Resistant to Pleurocidin-Family Lytic Peptides Are Chemosensitive and Exhibit Reduced Tumor-Forming Capacity

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1220
Author(s):  
Ashley L. Hilchie ◽  
Erin E. Gill ◽  
Melanie R. Power Coombs ◽  
Reza Falsafi ◽  
Robert E. W. Hancock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Cancer Cell Line ◽  
Matrix Composition ◽  
Breast Cancer Cell Lines ◽  
Lytic Peptides

Direct-acting anticancer (DAA) peptides are cytolytic peptides that show promise as novel anticancer agents. DAA peptides bind to anionic molecules that are abundant on cancer cells relative to normal healthy cells, which results in preferential killing of cancer cells. Due to the mechanism by which DAA peptides kill cancer cells, it was thought that resistance would be difficult to achieve. Here, we describe the generation and characterization of two MDA-MB-231 breast cancer cell-line variants with reduced susceptibility to pleurocidin-family and mastoparan DAA peptides. Peptide resistance correlated with deficiencies in peptide binding to cell-surface structures, suggesting that resistance was due to altered composition of the cell membrane. Peptide-resistant MDA-MB-231 cells were phenotypically distinct yet remained susceptible to chemotherapy. Surprisingly, neither of the peptide-resistant breast cancer cell lines was able to establish tumors in immune-deficient mice. Histological analysis and RNA sequencing suggested that tumorigenicity was impacted by alternations in angiogenesis and extracellular matrix composition in the peptide-resistant MDA-MB-231 variants. Collectively, these data further support the therapeutic potential of DAA peptides as adjunctive treatments for cancer.

scholarly journals Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases

2015 ◽  
Vol 22 (2) ◽  
pp. 273-284 ◽  
Author(s):  
Yunfei Wang ◽  
Ryan L. Stowe ◽  
Christie E. Pinello ◽  
Guimei Tian ◽  
Franck Madoux ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Class I

scholarly journals The Effect of Quisinostat as the HDAC Inhibitor on Migration

2021 ◽  
Vol 24 (3) ◽  
pp. 450-457
Author(s):  
Marjan Hajimoradi Javarsiani ◽  
◽  
Javad Sajedianfard ◽  
Shagayegh Haghjooy Javanmard ◽  
◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Fluorescent Microscopy ◽  
Regulation Of Gene Expression ◽  
Genetic Alterations ◽  
Ethical Considerations ◽  
Cycle Arrest ◽  
And Migration

Background and Aim: Cancer cannot be explained only by genetic alterations but involves epigenetic processes. Modifying histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between Histone Deacetylases (HDAC) and Histone Acetyltransferases (HAT). The HDACs expression and activity could be involved in several tumorigenesis mechanisms, so their inhibition induces cancer cell cycle arrest and migration. Methods & Materials: Quisinostat is a novel promising second-generation HDAC inhibitor class of hydroxamic acid with high cellular potency towards classes I and II HDACs. Therefore, its low IC50 (<0.5nM) and bioavailability have been chosen to carry out our studies. Cancer cells were treated with Quiznos at nM200, and cell migration was measured by fluorescent microscopy. Ethical Considerations: This study was the result of a preliminary study of Shiraz University (Code: 96GCU3M1293). Results: The data showed that treatment of cancer cells with Quiznos significantly (P<0.05) reduced cell migration. DMSO did not affect reducing cell migration. Conclusion: In this project try to explore the possible therapeutic application of this HDAC inhibitor against colon cancer. This study showed Quisinostat exerts broad-spectrum antiproliferative activity and migration.

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