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Zhou Y, Luo Q, Gu L, Tian X, Zhao Y, Zhang Y, Wang F. Histone Deacetylase Inhibitors Promote the Anticancer Activity of Cisplatin: Mechanisms and Potential. Pharmaceuticals (Basel) 2025; 18:563. [PMID: 40283998 PMCID: PMC12030095 DOI: 10.3390/ph18040563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Cisplatin is a widely used DNA-targeting anticancer drug. Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation, changing chromatin structure and accessibility of genomic DNA by the genotoxic drug. As a consequence, HDACi could promote cisplatin cytotoxicity. Hence, the underlying mechanisms by which HDACi alter the action pathways of cisplatin to promote its anticancer activity have attracted increasing attention during the past decades. It has been commonly accepted that HDACi elevate the acetylation level of histones to release genomic DNA to cisplatin attack, increasing the level of cisplatin-induced DNA lesions to promote cisplatin cytotoxicity. However, how the HDACi-enhanced cisplatin lesion on DNA impacts the downstream biological processes, and whether the promotion of HDACi to cisplatin activity is attributed to their inherent anticancer activity or to their induced elevation of histone acetylation, have been in debate. Several studies showed that HDACi-enhanced DNA lesion could promote cisplatin-induced apoptosis, cell cycle arrest, and reactive oxygen species (ROS) generation, subsequently promoting cisplatin efficiency. In contrast, HDACi-induced elimination of ROS and inhibition of ferroptosis were thought to be the main ways by which HDACi protect kidneys from acute injury caused by cisplatin. Based on our recent research, we herein review and discuss the advances in research on the mechanisms of HDACi-induced enhancement in cisplatin cytotoxicity. Given that histone acetyltransferase (HAT) inhibitors also show an effect enhancing cisplatin cytotoxicity, we will discuss the diverse roles of histone acetylation in cancer therapy in addition to the synergistic anticancer effect and potential of HDACi with genotoxic drugs and radiotherapy.
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Affiliation(s)
- Yang Zhou
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qun Luo
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liangzhen Gu
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiao Tian
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yao Zhao
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanyan Zhang
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
| | - Fuyi Wang
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China (Q.L.)
- University of Chinese Academy of Sciences, Beijing 100049, China
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- National Centre for Mass Spectrometry in Beijing, Beijing 100190, China
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Zhang H, Kim H, Yuan T, Zhang Z, Kaul SC, Wadhwa R. Molecular Characterization of Cancer Preventive and Therapeutic Potential of Three Antistress Compounds, Triethylene Glycol, Withanone, and Withaferin A. Int J Mol Sci 2025; 26:493. [PMID: 39859209 PMCID: PMC11764651 DOI: 10.3390/ijms26020493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
The molecular link between stress and carcinogenesis and the positive outcomes of stress intervention in cancer therapy have recently been well documented. Cancer stem cells (CSCs) facilitate cancer malignancy, drug resistance, and relapse and, hence, have emerged as a new therapeutic target. Here, we aimed to investigate the effect of three previously described antistress compounds (triethylene glycol, TEG; Withanone, Wi-N, and Withaferin A, Wi-A) on the stemness and differentiation characteristics of cancer cells. Breast carcinoma, glioblastoma, and neuroblastoma cells were treated with a non-toxic concentration of TEG (0.1%), Wi-N (5 µM), and Wi-A (0.1 µM) in 2D and 3D cultures. The results demonstrated that TEG, Wi-N, and Wi-A suppressed the stemness properties, which was linked with their inhibition of epithelial-mesenchymal transition (EMT) signaling. In particular, Wi-N and TEG caused a stronger reduction in the self-renewal capability of CSCs than Wi-A, as evidenced by a tumor spheroid formation assay and analyses of stemness-related genes (ALDH1, CD44, NANOG, CD133, SOX2). Furthermore, TEG and Wi-N caused the differentiation of cancer cells. Each of these was supported by (i) the upregulation of KRT18, KRT19, E-cadherin, and downregulation of vimentin in breast carcinoma; (ii) increased levels of GFAP, MAP2, and PSD-95 in astrocytoma; and (iii) increased NeuN, GAP-43, and NF200 levels in neuroblastoma. Furthermore, a reduction in cancer progression-related proteins (PI3K, N-myc) was recorded in treated cells. Our results suggest that TEG and Wi-N may be recruited to target cancer cell stemness and differentiation therapy.
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Affiliation(s)
- Huayue Zhang
- Graduate School of Science and Technology, University of Tsukuba, Ibaraki 305-8575, Japan; (H.Z.); (T.Y.); (Z.Z.)
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 4-1, Tsukuba 305-8565, Japan; (H.K.); (S.C.K.)
| | - Hyonchol Kim
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 4-1, Tsukuba 305-8565, Japan; (H.K.); (S.C.K.)
| | - Tian Yuan
- Graduate School of Science and Technology, University of Tsukuba, Ibaraki 305-8575, Japan; (H.Z.); (T.Y.); (Z.Z.)
| | - Zhenya Zhang
- Graduate School of Science and Technology, University of Tsukuba, Ibaraki 305-8575, Japan; (H.Z.); (T.Y.); (Z.Z.)
| | - Sunil C. Kaul
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 4-1, Tsukuba 305-8565, Japan; (H.K.); (S.C.K.)
| | - Renu Wadhwa
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Central 4-1, Tsukuba 305-8565, Japan; (H.K.); (S.C.K.)
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Gao Y, Wang P, Hu Z, Cui H, Chen X, Wang L, Zhao M, Qian R, Zhang L, Ye T, Zhu Y, Yao Y. Design, synthesis, and evaluation of a novel TRAIL-activated HDAC6 inhibitor for the treatment of pulmonary fibrosis. Bioorg Med Chem 2024; 113:117924. [PMID: 39321740 DOI: 10.1016/j.bmc.2024.117924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/27/2024]
Abstract
Pulmonary fibrosis (PF) is a common, severe, chronic, and progressive pulmonary interstitial disease characterized by rapid disease progression and high mortality. Despite the Food and Drug Administration (FDA)'s approval of two antifibrotic drugs, nintedanib and pirfenidone, effectively halting the progression of pulmonary fibrosis remains challenging. Histone deacetylase (HDAC) inhibitors have indeed emerged as an important class of antitumour drugs. However, their application in the treatment of fibrotic diseases is still relatively limited. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has the potential to inhibit fibrotic processes by inducing fibroblast apoptosis. In this study, we designed and synthesized a series of histone deacetylase 6 (HDAC6) inhibitors that activate TRAIL, among which compound 7e exhibited potent inhibitory activity against HDAC6, with an IC50 of 42.90 ± 4.96 nM and superior antiproliferative effects on fibroblasts. Therefore, we further investigated its anti-pulmonary fibrosis effect in mouse models of both idiopathic pulmonary fibrosis (IPF) and silicosis. Our results suggest that compound 7e is a promising candidate for the treatment of pulmonary fibrosis.
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Affiliation(s)
- Ying Gao
- West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Pengfeng Wang
- School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Zan Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hao Cui
- School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Xuxi Chen
- West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Liqun Wang
- West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Manyu Zhao
- Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network and West China Hospital, Sichuan University, Chengdu 610041, China
| | - Rui Qian
- West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Ling Zhang
- West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Tinghong Ye
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Zhu
- School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Yuqin Yao
- West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
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Xiao T, Chen Z, Xie Y, Yang C, Wu J, Gao L. Histone deacetylase inhibitors: targeting epigenetic regulation in the treatment of acute leukemia. Ther Adv Hematol 2024; 15:20406207241283277. [PMID: 39421716 PMCID: PMC11483798 DOI: 10.1177/20406207241283277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/22/2024] [Indexed: 10/19/2024] Open
Abstract
Acute leukemia (AL) is a rare yet perilous malignancy. Currently, the primary treatment for AL involves combination chemotherapy as the cornerstone of comprehensive measures, alongside hematopoietic stem cell transplantation as a radical approach. However, despite these interventions, mortality rates remain high, particularly among refractory/recurrent patients or elderly individuals with a poor prognosis. Acetylation, a form of epigenetic regulation, has emerged as a promising therapeutic avenue for treating AL. Recent studies have highlighted the potential of acetylation regulation as a novel treatment pathway. Histone deacetylase inhibitors (HDACis) play a pivotal role in modulating the differentiation and development of tumor cells through diverse pathways, simultaneously impacting the maturation and function of lymphocytes. HDACis demonstrate promise in enhancing survival rates and achieving a complete response in both acute myeloid leukemia and acute T-lymphoblastic leukemia patients. This article provides a comprehensive review of the advancements in HDACi therapy for AL, shedding light on its potential implications for clinical practice.
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Affiliation(s)
- Tong Xiao
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Zhigang Chen
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yutong Xie
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Chao Yang
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Junhong Wu
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Lei Gao
- Medical Center of Hematology, State Key Laboratory of Trauma, Burn and Combined Injury, Xinqiao Hospital, Army Medical University, No. 183, Xinqiao Street, Shapingba District, Chongqing 400037, China
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Chen X, Ding X, Fang J, Mao C, Gong X, Zhang Y, Zhang N, Yan F, Lou Y, Chen Z, Ding W, Ma Z. Natural Derivatives of Selective HDAC8 Inhibitors with Potent in Vivo Antitumor Efficacy against Breast Cancer. J Med Chem 2024; 67:14609-14632. [PMID: 39110628 DOI: 10.1021/acs.jmedchem.4c01438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 μM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.
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Affiliation(s)
- Xiaoming Chen
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Xia Ding
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Jiebin Fang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Churu Mao
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Xingzhi Gong
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Yuxiao Zhang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Ningjing Zhang
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Feihang Yan
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
| | - Yijie Lou
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Zhe Chen
- Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Wanjing Ding
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
- Hainan Institute of Zhejiang University, Sanya 572025, China
| | - Zhongjun Ma
- Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China
- Hainan Institute of Zhejiang University, Sanya 572025, China
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Chitra U, Arnold BJ, Raphael BJ. Quantifying higher-order epistasis: beware the chimera. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.17.603976. [PMID: 39071303 PMCID: PMC11275791 DOI: 10.1101/2024.07.17.603976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Epistasis, or interactions in which alleles at one locus modify the fitness effects of alleles at other loci, plays a fundamental role in genetics, protein evolution, and many other areas of biology. Epistasis is typically quantified by computing the deviation from the expected fitness under an additive or multiplicative model using one of several formulae. However, these formulae are not all equivalent. Importantly, one widely used formula - which we call the chimeric formula - measures deviations from a multiplicative fitness model on an additive scale, thus mixing two measurement scales. We show that for pairwise interactions, the chimeric formula yields a different magnitude, but the same sign (synergistic vs. antagonistic) of epistasis compared to the multiplicative formula that measures both fitness and deviations on a multiplicative scale. However, for higher-order interactions, we show that the chimeric formula can have both different magnitude and sign compared to the multiplicative formula - thus confusing negative epistatic interactions with positive interactions, and vice versa. We resolve these inconsistencies by deriving fundamental connections between the different epistasis formulae and the parameters of the multivariate Bernoulli distribution . Our results demonstrate that the additive and multiplicative epistasis formulae are more mathematically sound than the chimeric formula. Moreover, we demonstrate that the mathematical issues with the chimeric epistasis formula lead to markedly different biological interpretations of real data. Analyzing multi-gene knockout data in yeast, multi-way drug interactions in E. coli , and deep mutational scanning (DMS) of several proteins, we find that 10 - 60% of higher-order interactions have a change in sign with the multiplicative or additive epistasis formula. These sign changes result in qualitatively different findings on functional divergence in the yeast genome, synergistic vs. antagonistic drug interactions, and and epistasis between protein mutations. In particular, in the yeast data, the more appropriate multiplicative formula identifies nearly 500 additional negative three-way interactions, thus extending the trigenic interaction network by 25%.
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Tang Y, Cui G, Liu H, Han Y, Cai C, Feng Z, Shen H, Zeng S. Converting "cold" to "hot": epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells. Cancer Commun (Lond) 2024; 44:601-636. [PMID: 38715348 PMCID: PMC11194457 DOI: 10.1002/cac2.12546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 04/09/2024] [Accepted: 04/18/2024] [Indexed: 06/26/2024] Open
Abstract
Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called "cold" tumors which are unresponsive to immunotherapy, and the opposite are "hot" tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of "cold" tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming "cold" tumors into "hot" tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in "cold" tumor.
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Affiliation(s)
- Yijia Tang
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Guangzu Cui
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Haicong Liu
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Ying Han
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Changjing Cai
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Ziyang Feng
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Hong Shen
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
- National Clinical Resaerch Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Shan Zeng
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
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Tian X, Gu L, Zeng F, Liu X, Zhou Y, Dou Y, Han J, Zhao Y, Zhang Y, Luo Q, Wang F. Strophanthidin Induces Apoptosis of Human Lung Adenocarcinoma Cells by Promoting TRAIL-DR5 Signaling. Molecules 2024; 29:877. [PMID: 38398629 PMCID: PMC10892344 DOI: 10.3390/molecules29040877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Strophanthidin (SPTD), one of the cardiac glycosides, is refined from traditional Chinese medicines such as Semen Lepidii and Antiaris toxicaria, and was initially used for the treatment of heart failure disease in clinic. Recently, SPTD has been shown to be a potential anticancer agent, but the underlying mechanism of action is poorly understood. Herein, we explored the molecular mechanism by which SPTD exerts anticancer effects in A549 human lung adenocarcinoma cells by means of mass spectrometry-based quantitative proteomics in combination with bioinformatics analysis. We revealed that SPTD promoted the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2, or DR5) in A549 cells to activate caspase 3/6/8, in particular caspase 3. Consequently, the activated caspases elevated the expression level of apoptotic chromatin condensation inducer in the nucleus (ACIN1) and prelamin-A/C (LMNA), ultimately inducing apoptosis via cooperation with the SPTD-induced overexpressed barrier-to-autointegration factor 1 (Banf1). Moreover, the SPTD-induced DEPs interacted with each other to downregulate the p38 MAPK/ERK signaling, contributing to the SPTD inhibition of the growth of A549 cells. Additionally, the downregulation of collagen COL1A5 by SPTD was another anticancer benefit of SPTD through the modulation of the cell microenvironment.
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Affiliation(s)
- Xiao Tian
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
| | - Liangzhen Gu
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fangang Zeng
- School of Environment of Natural Resources, Remin University of China, Beijing 100875, China;
| | - Xingkai Liu
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
| | - Yang Zhou
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yang Dou
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Juanjuan Han
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
| | - Yao Zhao
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanyan Zhang
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
| | - Qun Luo
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fuyi Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; (L.G.); (X.L.); (Y.Z.); (Y.D.); (J.H.); (Y.Z.); (Y.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
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9
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Dandage R, Papkov M, Greco BM, Fishman D, Friesen H, Wang K, Styles E, Kraus O, Grys B, Boone C, Andrews B, Parts L, Kuzmin E. Single-cell imaging of protein dynamics of paralogs reveals mechanisms of gene retention. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.23.568466. [PMID: 38045359 PMCID: PMC10690282 DOI: 10.1101/2023.11.23.568466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Gene duplication is common across the tree of life, including yeast and humans, and contributes to genomic robustness. In this study, we examined changes in the subcellular localization and abundance of proteins in response to the deletion of their paralogs originating from the whole-genome duplication event, which is a largely unexplored mechanism of functional divergence. We performed a systematic single-cell imaging analysis of protein dynamics and screened subcellular redistribution of proteins, capturing their localization and abundance changes, providing insight into forces determining paralog retention. Paralogs showed dependency, whereby proteins required their paralog to maintain their native abundance or localization, more often than compensation. Network feature analysis suggested the importance of functional redundancy and rewiring of protein and genetic interactions underlying redistribution response of paralogs. Translation of non-canonical protein isoform emerged as a novel compensatory mechanism. This study provides new insights into paralog retention and evolutionary forces that shape genomes.
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10
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Zhang J, Duan H, Gui R, Wu M, Shen L, Jin Y, Pang A, Yu X, Zeng S, Zhang B, Lin N, Huang W, Wang Y, Yao X, Li J, Dong X, Zhou Y, Che J. Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia. Eur J Med Chem 2023; 262:115872. [PMID: 39491427 DOI: 10.1016/j.ejmech.2023.115872] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 11/05/2024]
Abstract
BRD9 is essential in regulating gene transcription and chromatin remodeling, and blocking BRD9 profoundly affects the survival of AML cells. However, the inhibitors of BRD9 suffer from various drawbacks, including poor phenotype and selectivity, and BRD9 PROTACs still face the challenge of druggability, which limits the development of blocking BRD9 in AML. This study described an oral activity BRD9 PROTAC C6 by recruiting the highly efficient E3 ligase. C6 demonstrated remarkable efficacy and selectivity in BRD9 degradation with a BRD9 degradation DC50 value of 1.02 ± 0.52 nM and no degradation of BRD4 or BRD7. Moreover, our findings highlighted its therapeutic potential, as evidenced by profound in vitro activity against the AML cell line MV4-11. Furthermore, C6 exhibited superior oral activity, with a Cmax value of 3436.95 ng/mL. These findings demonstrated that C6, as a novel BRD9 PROTAC with remarkable pharmacodynamic and pharmacokinetic properties, had the potential to be developed as a promising therapeutic agent for AML treatment.
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Affiliation(s)
- Jingyu Zhang
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Haiting Duan
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Renzhao Gui
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China
| | - Mingfei Wu
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Liteng Shen
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Yuheng Jin
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Ao Pang
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Xiaoli Yu
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Shenxin Zeng
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China
| | - Bo Zhang
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Nengming Lin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China
| | - Wenhai Huang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China
| | - Yuwei Wang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712000, PR China
| | - Xiaojun Yao
- Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, 999078, PR China
| | - Jia Li
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Yubo Zhou
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, PR China; School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
| | - Jinxin Che
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
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11
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Sen P, Ghosh SS. γ-Secretase Inhibitor Potentiates the Activity of Suberoylanilide Hydroxamic Acid by Inhibiting Its Ability to Induce Epithelial to Mesenchymal Transition and Stemness via Notch Pathway Activation in Triple-Negative Breast Cancer Cells. ACS Pharmacol Transl Sci 2023; 6:1396-1415. [PMID: 37854616 PMCID: PMC10580388 DOI: 10.1021/acsptsci.3c00099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Indexed: 10/20/2023]
Abstract
Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA), possess great therapeutic value for triple-negative breast cancer patients. However, their inherent ability to induce epithelial to mesenchymal transition in various malignancies has been of greater concern. Herein, we hypothesize that SAHA facilitates epithelial to mesenchymal transition (EMT) via activation of the Notch pathway. From the literature survey, it is evident that histone deacetylase mediates the formation of the co-repressor complex upon interacting with the DNA binding domain, thereby inhibiting the transcription of the Notch downstream genes. Hence, we hypothesize that the use of SAHA facilitates the transcriptional activation of the Notch target genes, by disrupting the co-repressor complex and recruiting the coactivator complex, thereby facilitating EMT. In this study, we have observed that SAHA upregulates the expression profile of the Notch downstream proteins (such as Notch intracellular domain, Hes-1, c-Myc, etc.) and the Notch ligands (such as Jagged-1 and Jagged-2), thereby aberrantly activating the signaling pathway. Therefore, we have focused on combination therapy using a γ-secretase inhibitor LY411575 that would enhance the efficacy of SAHA by blocking the canonical Notch pathway mediated via its intracellular domain. It was observed that co-treatment significantly mediates apoptosis, generates cellular reactive oxygen species, depolarizes mitochondria, and diminishes the stemness properties. Besides, it also mediates autophagy-independent cell death and diminishes the expression of inflammatory cytokines, along with the downregulation in the expression of the Notch downstream genes and mesenchymal markers. Altogether, our study provides a mechanistic basis for combating EMT potentiated by SAHA, which could be utilized as a rational strategy for the treatment of solid tumors, especially triple-negative breast cancer.
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Affiliation(s)
- Plaboni Sen
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Siddhartha Sankar Ghosh
- Department
of Biosciences and Bioengineering, Indian
Institute of Technology Guwahati, Guwahati 781039, Assam, India
- Centre
for Nanotechnology, Indian Institute of
Technology Guwahati, Guwahati 781039, Assam, India
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12
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Simpson D, Ling J, Jing Y, Adamson B. Mapping the Genetic Interaction Network of PARP inhibitor Response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553986. [PMID: 37645833 PMCID: PMC10462155 DOI: 10.1101/2023.08.19.553986] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Genetic interactions have long informed our understanding of the coordinated proteins and pathways that respond to DNA damage in mammalian cells, but systematic interrogation of the genetic network underlying that system has yet to be achieved. Towards this goal, we measured 147,153 pairwise interactions among genes implicated in PARP inhibitor (PARPi) response. Evaluating genetic interactions at this scale, with and without exposure to PARPi, revealed hierarchical organization of the pathways and complexes that maintain genome stability during normal growth and defined changes that occur upon accumulation of DNA lesions due to cytotoxic doses of PARPi. We uncovered unexpected relationships among DNA repair genes, including context-specific buffering interactions between the minimally characterized AUNIP and BRCA1-A complex genes. Our work thus establishes a foundation for mapping differential genetic interactions in mammalian cells and provides a comprehensive resource for future studies of DNA repair and PARP inhibitors.
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Affiliation(s)
- Danny Simpson
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Jia Ling
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Yangwode Jing
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
| | - Britt Adamson
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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13
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Hsieh YY, Lee KC, Cheng KC, Lee KF, Yang YL, Chu HT, Lin TW, Chen CC, Hsieh MC, Huang CY, Kuo HC, Teng CC. Antrodin C Isolated from Antrodia Cinnamomea Induced Apoptosis through ROS/AKT/ERK/P38 Signaling Pathway and Epigenetic Histone Acetylation of TNFα in Colorectal Cancer Cells. Antioxidants (Basel) 2023; 12:antiox12030764. [PMID: 36979011 PMCID: PMC10045953 DOI: 10.3390/antiox12030764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/09/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of Antrodia cinnamomea, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear. METHODS The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V-FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation. RESULTS Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo.
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Affiliation(s)
- Yung-Yu Hsieh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Ko-Chao Lee
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung 833401, Taiwan
- College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Kung-Chuan Cheng
- Division of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung 833401, Taiwan
| | - Kam-Fai Lee
- Department of Pathology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Ya-Ling Yang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833401, Taiwan
| | - Hsin-Tung Chu
- Biotech Research Institute, Grap King Bio Ltd., Taoyuan 325002, Taiwan
| | - Ting-Wei Lin
- Biotech Research Institute, Grap King Bio Ltd., Taoyuan 325002, Taiwan
| | - Chin-Chu Chen
- Biotech Research Institute, Grap King Bio Ltd., Taoyuan 325002, Taiwan
| | - Meng-Chiao Hsieh
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Cheng-Yi Huang
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Hsing-Chun Kuo
- Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chiayi 613016, Taiwan
- Research Fellow, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333324, Taiwan
- Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi 613016, Taiwan
| | - Chih-Chuan Teng
- Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chiayi 613016, Taiwan
- Research Fellow, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
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14
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Yao D, Binan L, Bezney J, Simonton B, Freedman J, Frangieh CJ, Dey K, Geiger-Schuller K, Eraslan B, Gusev A, Regev A, Cleary B. Compressed Perturb-seq: highly efficient screens for regulatory circuits using random composite perturbations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.23.525200. [PMID: 36747806 PMCID: PMC9900787 DOI: 10.1101/2023.01.23.525200] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Pooled CRISPR screens with single-cell RNA-seq readout (Perturb-seq) have emerged as a key technique in functional genomics, but are limited in scale by cost and combinatorial complexity. Here, we reimagine Perturb-seq's design through the lens of algorithms applied to random, low-dimensional observations. We present compressed Perturb-seq, which measures multiple random perturbations per cell or multiple cells per droplet and computationally decompresses these measurements by leveraging the sparse structure of regulatory circuits. Applied to 598 genes in the immune response to bacterial lipopolysaccharide, compressed Perturb-seq achieves the same accuracy as conventional Perturb-seq at 4 to 20-fold reduced cost, with greater power to learn genetic interactions. We identify known and novel regulators of immune responses and uncover evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing GWAS or trans-eQTL studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.
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Affiliation(s)
- Douglas Yao
- Program in Systems, Synthetic, and Quantitative Biology, Harvard University, Cambridge, MA
| | - Loic Binan
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
| | - Jon Bezney
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
- Current address: Department of Genetics, Stanford University School of Medicine, Stanford, CA
| | - Brooke Simonton
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
| | - Jahanara Freedman
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
| | - Chris J Frangieh
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA
| | - Kushal Dey
- Harvard T.H. Chan School of Public Health, Boston, MA
| | | | | | - Alexander Gusev
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Division of Genetics, Brigham and Women's Hospital, Boston, MA
- These authors jointly supervised this work
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA
- Current address: Genentech, South San Francisco, CA
- These authors jointly supervised this work
| | - Brian Cleary
- Faculty of Computing and Data Sciences, Boston University, Boston, MA
- Department of Biology, Boston University, Boston, MA
- Department of Biomedical Engineering, Boston University, Boston, MA
- Program in Bioinformatics, Boston University, Boston, MA
- Biological Design Center, Boston University, Boston, MA
- These authors jointly supervised this work
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15
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Liu G, Chen T, Zhang X, Ma X, Shi H. Small molecule inhibitors targeting the cancers. MedComm (Beijing) 2022; 3:e181. [PMID: 36254250 PMCID: PMC9560750 DOI: 10.1002/mco2.181] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/23/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary targeted therapies for cancer. Due to their advantages in a wide range of targets, convenient medication, and the ability to penetrate into the central nervous system, many efforts have been devoted to developing more small molecule inhibitors. To date, 88 small molecule inhibitors have been approved by the United States Food and Drug Administration to treat cancers. Despite remarkable progress, small molecule inhibitors in cancer treatment still face many obstacles, such as low response rate, short duration of response, toxicity, biomarkers, and resistance. To better promote the development of small molecule inhibitors targeting cancers, we comprehensively reviewed small molecule inhibitors involved in all the approved agents and pivotal drug candidates in clinical trials arranged by the signaling pathways and the classification of small molecule inhibitors. We discussed lessons learned from the development of these agents, the proper strategies to overcome resistance arising from different mechanisms, and combination therapies concerned with small molecule inhibitors. Through our review, we hoped to provide insights and perspectives for the research and development of small molecule inhibitors in cancer treatment.
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Affiliation(s)
- Gui‐Hong Liu
- Department of BiotherapyState Key Laboratory of BiotherapyCancer Center, West China HospitalSichuan UniversityChengduChina
| | - Tao Chen
- Department of CardiologyThe First Affiliated Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xin Zhang
- Department of BiotherapyState Key Laboratory of BiotherapyCancer Center, West China HospitalSichuan UniversityChengduChina
| | - Xue‐Lei Ma
- Department of BiotherapyState Key Laboratory of BiotherapyCancer Center, West China HospitalSichuan UniversityChengduChina
| | - Hua‐Shan Shi
- Department of BiotherapyState Key Laboratory of BiotherapyCancer Center, West China HospitalSichuan UniversityChengduChina
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16
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Truong N, Goodis CC, Cottingham AL, Shaw JR, Fletcher S, Pearson RM. Modified Suberoylanilide Hydroxamic Acid Reduced Drug-Associated Immune Cell Death and Organ Damage under Lipopolysaccharide Inflammatory Challenge. ACS Pharmacol Transl Sci 2022; 5:1128-1141. [PMID: 36407956 PMCID: PMC9667537 DOI: 10.1021/acsptsci.2c00119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Indexed: 11/29/2022]
Abstract
Histone deacetylase inhibitors (HDACi) induce potent anti-inflammatory responses when used to treat inflammatory diseases. Suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, decreases pro-inflammatory cytokine levels and attenuates cytokine storm in sepsis; however, its toxicity profile toward immune cells has limited its use as a sepsis therapeutic. Here, we developed a modification to SAHA by para-hydroxymethylating the capping group to generate SAHA-OH. We discovered that SAHA-OH provides a favorable improvement to the toxicity profile compared to SAHA. SAHA-OH significantly reduced primary macrophage apoptosis and splenic B cell death as well as mitigated organ damage using a lipopolysaccharide (LPS)-induced endotoxemia mouse model. Furthermore, SAHA-OH retained anti-inflammatory responses similar to SAHA as measured by reductions in LPS-induced proinflammatory cytokine secretions in vitro and in vivo. These effects were attributed to a decreased selectivity of HDAC1, 2, 3, 8 and an increased selectivity for HDAC6 for SAHA-OH as determined by IC50 values. Our results support the potential for SAHA-OH to modulate acute proinflammatory responses while mitigating SAHA-associated drug toxicity for use in the treatment of inflammation-associated diseases and conditions.
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Affiliation(s)
- Nhu Truong
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States
| | - Christopher C. Goodis
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States
| | - Andrea L. Cottingham
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States
| | - Jacob R. Shaw
- Department
of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States
| | - Steven Fletcher
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States
| | - Ryan M. Pearson
- Department
of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States
- Department
of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States
- Marlene
and Stewart Greenbaum Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States
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17
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Cui H, Hu Z, Yang K, Huang J, Wu Y, Chen Q, Wei R, Wang P, Wang H, Li H, Chen Y, Lu T, Yao Y, Zhu Y. Design and synthesis of highly TRAIL expression HDAC inhibitors based on ONC201 to promote apoptosis of colorectal cancer. Eur J Med Chem 2022; 238:114484. [DOI: 10.1016/j.ejmech.2022.114484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/06/2022] [Accepted: 05/17/2022] [Indexed: 11/03/2022]
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18
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Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells. Pharmaceuticals (Basel) 2022; 15:ph15070824. [PMID: 35890123 PMCID: PMC9323654 DOI: 10.3390/ph15070824] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 11/30/2022] Open
Abstract
Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.
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19
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High-Risk Acute Myeloid Leukemia: A Pediatric Prospective. Biomedicines 2022; 10:biomedicines10061405. [PMID: 35740427 PMCID: PMC9220202 DOI: 10.3390/biomedicines10061405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 11/16/2022] Open
Abstract
Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported in some studies. The standard therapeutic approach is a combined cytarabine and anthracycline-based regimen followed by consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk AML and allo-SCT for non-high-risk patients only in second complete remission after relapse. In the last decade, several drugs have been used in clinical trials to improve outcomes in pediatric AML treatment.
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20
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Yao J, Li G, Cui Z, Chen P, Wang J, Hu Z, Zhang L, Wei L. The Histone Deacetylase Inhibitor I1 Induces Differentiation of Acute Leukemia Cells With MLL Gene Rearrangements via Epigenetic Modification. Front Pharmacol 2022; 13:876076. [PMID: 35571127 PMCID: PMC9091196 DOI: 10.3389/fphar.2022.876076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/02/2022] [Indexed: 12/19/2022] Open
Abstract
Acute leukemia (AL) is characterized by excessive proliferation and impaired differentiation of leukemic cells. AL includes acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Previous studies have demonstrated that about 10% of AML and 22% of ALL are mixed lineage leukemia gene rearrangements (MLLr) leukemia. The prognosis of MLLr leukemia is poor and new therapeutics are urgently needed. Differentiation therapy with all-trans-retinoic acid (ATRA) has prolonged the 5-years disease-free survival rate in acute promyelocytic leukemia (APL), a subtype of AML. However, the differentiation therapy has not been effective in other acute leukemia. Here, we aim to explore the cell differentiation effect of the potent HDACs inhibitor, I1, and the possible mechanism on the MLLr-AML and MLLr-ALL cells (MOLM-13, THP-1, MV4-11 and SEM). It is shown that I1 can significantly inhibit the proliferation and the colony-forming ability of MOLM-13, THP-1, MV4-11 and SEM cells by promoting cell differentiation coupled with cell cycle block at G0/G1 phase. We show that the anti-proliferative effect of I1 attributed to cell differentiation is most likely associated with the HDAC inhibition activity, as assessed by the acetylation of histone H3 and H4, which may dictates the activation of hematopoietic cell lineage pathway in both MOLM-13 and THP-1 cell lines. Moreover, the activity of HDAC inhibition of I1 is stronger than that of SAHA in MOLM-13 and THP-1 cells. Our findings suggest that I1, as a chromatin-remodeling agent, could be a potent epigenetic drug to overcome differentiation block in MLLr-AL patients and would be promising for the treatment of AL.
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Affiliation(s)
- Jingfang Yao
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.,School of Pharmacy, Weifang Medical University, Weifang, China
| | - Gentao Li
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zihui Cui
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Peilei Chen
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Jinhong Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zhenbo Hu
- Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Lei Zhang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang, China
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21
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Shanmugam G, Rakshit S, Sarkar K. HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases. Transl Oncol 2022; 16:101312. [PMID: 34922087 PMCID: PMC8688863 DOI: 10.1016/j.tranon.2021.101312] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Histone deacetylases (HDACs) are enzymes that play a key role in the epigenetic regulation of gene expression by remodeling chromatin. Inhibition of HDACs is a prospective therapeutic approach for reversing epigenetic alteration in several diseases. In preclinical research, numerous types of HDAC inhibitors were discovered to exhibit powerful and selective anticancer properties. However, such research has revealed that the effects of HDAC inhibitors may be far broader and more intricate than previously thought. This review will provide insight into the HDAC inhibitors and their mechanism of action with special emphasis on the significance of HDAC inhibitors in the treatment of Chronic Obstructive Pulmonary Disease and lung cancer. Nanocarrier-mediated HDAC inhibitor delivery and new approaches for targeting HDACs are also discussed.
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Affiliation(s)
- Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Sudeshna Rakshit
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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22
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Zhang Y, Archer KJ. Bayesian variable selection for high-dimensional data with an ordinal response: identifying genes associated with prognostic risk group in acute myeloid leukemia. BMC Bioinformatics 2021; 22:539. [PMID: 34727888 PMCID: PMC8565083 DOI: 10.1186/s12859-021-04432-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/04/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a heterogeneous cancer of the blood, though specific recurring cytogenetic abnormalities in AML are strongly associated with attaining complete response after induction chemotherapy, remission duration, and survival. Therefore recurring cytogenetic abnormalities have been used to segregate patients into favorable, intermediate, and adverse prognostic risk groups. However, it is unclear how expression of genes is associated with these prognostic risk groups. We postulate that expression of genes monotonically associated with these prognostic risk groups may yield important insights into leukemogenesis. Therefore, in this paper we propose penalized Bayesian ordinal response models to predict prognostic risk group using gene expression data. We consider a double exponential prior, a spike-and-slab normal prior, a spike-and-slab double exponential prior, and a regression-based approach with variable inclusion indicators for modeling our high-dimensional ordinal response, prognostic risk group, and identify genes through hypothesis tests using Bayes factor. RESULTS Gene expression was ascertained using Affymetrix HG-U133Plus2.0 GeneChips for 97 favorable, 259 intermediate, and 97 adverse risk AML patients. When applying our penalized Bayesian ordinal response models, genes identified for model inclusion were consistent among the four different models. Additionally, the genes included in the models were biologically plausible, as most have been previously associated with either AML or other types of cancer. CONCLUSION These findings demonstrate that our proposed penalized Bayesian ordinal response models are useful for performing variable selection for high-dimensional genomic data and have the potential to identify genes relevantly associated with an ordinal phenotype.
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Affiliation(s)
| | - Kellie J Archer
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH, USA.
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23
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Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes. Cancers (Basel) 2021; 13:cancers13205127. [PMID: 34680276 PMCID: PMC8534227 DOI: 10.3390/cancers13205127] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Myeloid-derived suppressor cells restrict the effectiveness of immune-checkpoint inhibitors for a subset of patients mainly through thwarting T cell infiltration into tumor sites. Treatments targeting MDSCs have shown potent inhibitory effects on multiple tumors, including hepatocellular carcinoma. In this review, we summarize the pathological mechanisms of MDSCs and their clinical significance as prognostic and predictive biomarkers for HCC patients, and we provide the latest progress of MDSCs-targeting treatment in HCC. Abstract One of the major challenges in hepatocellular carcinoma (HCC) treatment is drug resistance and low responsiveness to systemic therapies, partly due to insufficient T cell infiltration. Myeloid-derived suppressor cells (MDSCs) are immature marrow-derived cell populations with heterogeneity and immunosuppression characteristics and are essential components of the suppressive tumor immune microenvironment (TIME). Increasing evidence has demonstrated that MDSCs are indispensable contributing factors to HCC development in a T cell-dependent or non-dependent manner. Clinically, the frequency of MDSCs is firmly linked to HCC clinical outcomes and the effectiveness of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Furthermore, MDSCs can also be used as prognostic and predictive biomarkers for patients with HCC. Therefore, treatments reprograming MDSCs may offer potential therapeutic opportunities in HCC. Here, we recapitulated the dynamic relevance of MDSCs in the initiation and development of HCC and paid special attention to the effect of MDSCs on T cells infiltration in HCC. Finally, we pointed out the potential therapeutic effect of targeting MDSCs alone or in combination, hoping to provide new insights into HCC treatment.
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24
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Carraway HE, Sawalha Y, Gojo I, Lee MJ, Lee S, Tomita Y, Yuno A, Greer J, Smith BD, Pratz KW, Levis MJ, Gore SD, Ghosh N, Dezern A, Blackford AL, Baer MR, Gore L, Piekarz R, Trepel JB, Karp JE. Phase 1 study of the histone deacetylase inhibitor entinostat plus clofarabine for poor-risk Philadelphia chromosome-negative (newly diagnosed older adults or adults with relapsed refractory disease) acute lymphoblastic leukemia or biphenotypic leukemia. Leuk Res 2021; 110:106707. [PMID: 34563945 DOI: 10.1016/j.leukres.2021.106707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 08/22/2021] [Accepted: 09/08/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL. EXPERIMENTAL DESIGN Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy. RESULTS Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. CONCLUSION Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.
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Affiliation(s)
- Hetty E Carraway
- Hematology Oncology Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States.
| | - Yazeed Sawalha
- Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ivana Gojo
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Min-Jung Lee
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Sunmin Lee
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Yusuke Tomita
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Akira Yuno
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Jackie Greer
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - B Douglas Smith
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Keith W Pratz
- The University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mark J Levis
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Steven D Gore
- Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, NIH, Bethesda, MD, United States
| | - Nilanjan Ghosh
- Atrium Health, Carolinas HealthCare System, Charlotte, NC, United States
| | - Amy Dezern
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Amanda L Blackford
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
| | - Maria R Baer
- University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
| | - Lia Gore
- University of Colorado Cancer Center, Aurora, CO, United States
| | - Richard Piekarz
- Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, NIH, Bethesda, MD, United States
| | - Jane B Trepel
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - Judith E Karp
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, United States
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25
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Clinical developments in epigenetic-directed therapies in acute myeloid leukemia. Blood Adv 2021; 4:970-982. [PMID: 32150613 DOI: 10.1182/bloodadvances.2019001245] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/27/2020] [Indexed: 01/01/2023] Open
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous disease arising from acquired genetic and epigenetic aberrations which stifle normal development and differentiation of hematopoietic precursors. Despite the complex and varied biological underpinnings, induction therapy for AML has remained fairly uniform over 4 decades and outcomes remain poor for most patients. Recently, enhanced understanding of the leukemic epigenome has resulted in the translational investigation of a number of epigenetic modifying agents currently in various stages of clinical development. These novel therapies are based on mechanistic rationale and offer the potential to improve AML patient outcomes. In light of many recent advances in this field, we provide an updated, clinically oriented review of the evolving landscape of epigenetic modifying agents for the treatment of AML.
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26
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Liu S, Polsdofer EV, Zhou L, Ruan S, Lyu H, Hou D, Liu H, Thor AD, He Z, Liu B. Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:303-314. [PMID: 34141868 PMCID: PMC8167201 DOI: 10.1016/j.omto.2021.04.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/24/2021] [Indexed: 12/24/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo. Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL.
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Affiliation(s)
- Shuang Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, China.,Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Erik V Polsdofer
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Lukun Zhou
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Sanbao Ruan
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Hui Lyu
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Defu Hou
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Hao Liu
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
| | - Ann D Thor
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Zhimin He
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, China
| | - Bolin Liu
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA
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27
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Gediya P, Vyas VK, Carafa V, Sitwala N, Della Torre L, Poziello A, Kurohara T, Suzuki T, Sanna V, Raguraman V, Suthindhiran K, Ghosh D, Bhatia D, Altucci L, Ghate MD. Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors. Bioorg Chem 2021; 110:104801. [PMID: 33756235 DOI: 10.1016/j.bioorg.2021.104801] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/27/2021] [Accepted: 03/01/2021] [Indexed: 10/22/2022]
Abstract
The discovery and development of isoform-selective histone deacetylase (HDAC) inhibitor is a challenging task because of the sequence homology among HDAC enzymes. In the present work, novel tetrahydro benzo[b]thiophene-3-carbonitrile based benzamides were designed, synthesized, and evaluated as HDAC inhibitors. Pharmacophore modeling was our main design strategy, and two novel series of tetrahydro benzo[b]thiophene-3-carbonitrile derivatives with piperidine linker (series 1) and piperazine linker (series 2) were identified as HDAC inhibitors. Among all the synthesised compounds, 9h with 4-(aminomethyl) piperidine linker and 14n with piperazine linker demonstrated good activity against human HDAC1 and HDAC6, respectively. Both the compounds also exhibited good antiproliferative activity against several human cancer cell lines. Both these compounds (9h and 14n) also induced cell cycle arrest and apoptosis in U937 and MDA-MB-231 cancer cells. Overall, for the first time, this research discovered potent isoform-selective HDAC inhibitors using cyclic linker instead of the aliphatic chain and aromatic ring system, which were reported in known HDAC inhibitors.
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Affiliation(s)
- Piyush Gediya
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India
| | - Vivek K Vyas
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India
| | - Vincenzo Carafa
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Nikum Sitwala
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India
| | - Laura Della Torre
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Angelita Poziello
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Takashi Kurohara
- The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibarakishi, Osaka 567-0047, Japan
| | - Takayoshi Suzuki
- The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibarakishi, Osaka 567-0047, Japan
| | - Vinod Sanna
- Piramal Pharma Solution, Plot-18 Pharmaceutical Special Economic Zone, Sarkhej-Bawla, NH-8A, Ahmedabad, Gujarat 382213, India
| | - Varalakshmi Raguraman
- School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu, India
| | - K Suthindhiran
- School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu, India
| | - Debarpan Ghosh
- Department of Biological Engineering, Indian Institute of Technology, Gandhinagar 382355, Gujarat, India
| | - Dhiraj Bhatia
- Department of Biological Engineering, Indian Institute of Technology, Gandhinagar 382355, Gujarat, India
| | - Lucia Altucci
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Manjunath D Ghate
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
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28
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Singh D, Tewari M, Singh S, Narayan G. Revisiting the role of TRAIL/TRAIL-R in cancer biology and therapy. Future Oncol 2021; 17:581-596. [PMID: 33401962 DOI: 10.2217/fon-2020-0727] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, can induce apoptosis in cancer cells, sparing normal cells when bound to its associated death receptors (DR4/DR5). This unique mechanism makes TRAIL a potential anticancer therapeutic agent. However, clinical trials of recombinant TRAIL protein and TRAIL receptor agonist monoclonal antibodies have shown disappointing results due to its short half-life, poor pharmacokinetics and the resistance of the cancer cells. This review summarizes TRAIL-induced apoptotic and survival pathways as well as mechanisms leading to apoptotic resistance. Recent development of methods to overcome cancer cell resistance to TRAIL-induced apoptosis, such as protein modification, combination therapy and TRAIL-based gene therapy, appear promising. We also discuss the challenges and opportunities in the development of TRAIL-based therapies for the treatment of human cancers.
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Affiliation(s)
- Deepika Singh
- Department of Molecular & Human Genetics, Cancer Genetics Laboratory, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Sunita Singh
- Department of Zoology, Mahila Mahavidyalaya, Banaras Hindu University, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Department of Molecular & Human Genetics, Cancer Genetics Laboratory, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
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29
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Zwergel C, Di Bello E, Fioravanti R, Conte M, Nebbioso A, Mazzone R, Brosch G, Mercurio C, Varasi M, Altucci L, Valente S, Mai A. Novel Pyridine-Based Hydroxamates and 2'-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity. ChemMedChem 2020; 16:989-999. [PMID: 33220015 DOI: 10.1002/cmdc.202000854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Indexed: 12/31/2022]
Abstract
Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6-8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9 a, 9 c-f, and 11 a-f) and 2'-aminoanilides (10 a-f and 12 a-f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC50 : 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC50 HDAC3 =0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level.
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Affiliation(s)
- Clemens Zwergel
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy
| | - Elisabetta Di Bello
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy
| | - Mariarosaria Conte
- Department of Precision Medicine Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Naples, Italy
| | - Angela Nebbioso
- Department of Precision Medicine Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Naples, Italy
| | - Roberta Mazzone
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy
| | - Gerald Brosch
- Institute of Molecular Biology, Biocenter, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Ciro Mercurio
- Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milan, Italy
| | - Mario Varasi
- Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milan, Italy
| | - Lucia Altucci
- Department of Precision Medicine Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Naples, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro, 500185, Rome, Italy
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30
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Fioravanti R, Tomassi S, Di Bello E, Romanelli A, Plateroti AM, Benedetti R, Conte M, Novellino E, Altucci L, Valente S, Mai A. Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells. Molecules 2020; 25:molecules25143122. [PMID: 32650558 PMCID: PMC7397249 DOI: 10.3390/molecules25143122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 11/16/2022] Open
Abstract
Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((E)-3-bromobenzylidene)piperidin-4-one 3 displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((E)-2-bromobenzylidene) cyclic compounds 4a–n to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of 4a–n exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (4d), benzyl (4e), or acyl (4k–m) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (4f) and 3-phenylpropyl (4g) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (4h–j). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.
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Affiliation(s)
- Rossella Fioravanti
- Dipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, Italy; (R.F.); (E.D.B.); (A.R.)
| | - Stefano Tomassi
- Dipartimento di Farmacia, Università di Napoli ‘Federico II’, 80131 Napoli, Italy; (S.T.); (E.N.)
| | - Elisabetta Di Bello
- Dipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, Italy; (R.F.); (E.D.B.); (A.R.)
| | - Annalisa Romanelli
- Dipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, Italy; (R.F.); (E.D.B.); (A.R.)
| | - Andrea Maria Plateroti
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso–Nesmos, ‘Sapienza’ Università di Roma, 00185 Roma, Italy;
| | - Rosaria Benedetti
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80138 Napoli, Italy; (R.B.); (M.C.); (L.A.)
| | - Mariarosaria Conte
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80138 Napoli, Italy; (R.B.); (M.C.); (L.A.)
| | - Ettore Novellino
- Dipartimento di Farmacia, Università di Napoli ‘Federico II’, 80131 Napoli, Italy; (S.T.); (E.N.)
| | - Lucia Altucci
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80138 Napoli, Italy; (R.B.); (M.C.); (L.A.)
| | - Sergio Valente
- Dipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, Italy; (R.F.); (E.D.B.); (A.R.)
- Correspondence: (S.V.); (A.M.)
| | - Antonello Mai
- Dipartimento di Chimica e Tecnologie del Farmaco, ‘Sapienza’ Università di Roma, 00185 Roma, Italy; (R.F.); (E.D.B.); (A.R.)
- Correspondence: (S.V.); (A.M.)
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Huang Y, Chen S, Wu S, Dong G, Sheng C. Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity. Acta Pharm Sin B 2020; 10:1294-1308. [PMID: 32874829 PMCID: PMC7452071 DOI: 10.1016/j.apsb.2019.11.011] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/01/2019] [Accepted: 11/10/2019] [Indexed: 12/31/2022] Open
Abstract
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.
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Key Words
- Antitumor activity
- BSA, bovine serum albumin
- CCK-8, cell counting kit-8
- CPT, camptothecin
- DIPEA, N,N-diisopropylethylamine
- DMF, dimethylformamide
- Dual inhibitors
- Eto, etoposide
- Evodiamine
- HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
- HDAC, histone deacetylase
- Histone deacetylase
- IP, intraperitoneal injection
- OD, optical density
- PI, propidium iodide
- SD, Sprague–Dawley
- SDS, sodium dodecyl sulfate
- TAE, Tris-acetate-EDTA
- TGI, tumor growth inhibition
- TOP, topoisomerase
- Topoisomerase
- ZBG, zinc-binding group
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32
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Liu T, Wan Y, Xiao Y, Xia C, Duan G. Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy. J Med Chem 2020; 63:8977-9002. [PMID: 32320239 DOI: 10.1021/acs.jmedchem.0c00491] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Histone deacetylases (HDACs) play an important role in regulating target gene expression. They have been highlighted as a novel category of anticancer targets, and their inhibition can induce apoptosis, differentiation, and growth arrest in cancer cells. In view of the fact that HDAC inhibitors and other antitumor agents, such as BET inhibitors, topoisomerase inhibitors, and RTK pathway inhibitors, exert a synergistic effect on cellular processes in cancer cells, the combined inhibition of two targets is regarded as a rational strategy to improve the effectiveness of these single-target drugs for cancer treatment. In this review, we discuss the theoretical basis for designing HDAC-involved dual-target drugs and provide insight into the structure-activity relationships of these dual-target agents.
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Affiliation(s)
- Tingting Liu
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Yichao Wan
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, Hunan, China
| | - Yuliang Xiao
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Chengcai Xia
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
| | - Guiyun Duan
- Department of Medicinal Chemistry, School of Pharmacy, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, China
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33
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Xie Z, Ikegami T, Ago Y, Okada N, Tachibana M. Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression. Oncoimmunology 2020; 9:1734268. [PMID: 32158627 PMCID: PMC7051186 DOI: 10.1080/2162402x.2020.1734268] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 02/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that promote tumor progression by inhibiting anti-tumor immunity and may be the cause of patient resistance to immune checkpoint inhibitors (ICIs). Therefore, MDSCs are a promising target for cancer immunotherapy, especially in combination with ICIs. Previous studies have shown that the anticonvulsant drug valproic acid (VPA) has additional anti-cancer and immunoregulatory activities due to its inhibition of histone deacetylases. We have previously shown that VPA can attenuate the immunosuppressive function of differentiated MDSCs in vitro. In the present study, we utilized anti-PD-1-sensitive EL4 and anti-PD-1-resistant B16-F10 tumor-bearing mouse models and investigated the effects of VPA on MDSCs with the aim of enhancing the anti-cancer activity of an anti-PD-1 antibody. We showed that VPA could inhibit EL4 and B16-F10 tumor progression, which was dependent on the immune system. We further demonstrated that VPA down-regulated the expression of CCR2 on monocytic (M)-MDSCs, leading to the reduced infiltration of M-MDSCs into tumors. Importantly, we demonstrated that VPA could relieve the immunosuppressive action of MDSCs on CD8+ T-cell and NK cell proliferation and enhance their activation in tumors. We also observed that the combination of VPA plus an anti-PD-1 antibody was more effective than either agent alone in both the EL4 and B16-F10 tumor models. These results suggest that VPA can effectively relieve the immunosuppressive tumor microenvironment by reducing tumor infiltration of M-MDSCs, resulting in tumor regression. Our findings also show that VPA in combination with an immunotherapeutic agent could be a potential new anti-cancer therapy.
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Affiliation(s)
- Zhiqi Xie
- Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Tamami Ikegami
- Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Yukio Ago
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
| | - Naoki Okada
- Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Masashi Tachibana
- Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
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34
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Sultana F, Manasa KL, Shaik SP, Bonam SR, Kamal A. Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update. Curr Med Chem 2020; 26:7212-7280. [PMID: 29852860 DOI: 10.2174/0929867325666180530094120] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 02/12/2018] [Accepted: 05/22/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Histone deacetylases (HDAC) are an important class of enzymes that play a pivotal role in epigenetic regulation of gene expression that modifies the terminal of core histones leading to remodelling of chromatin topology and thereby controlling gene expression. HDAC inhibitors (HDACi) counter this action and can result in hyperacetylation of histones, thereby inducing an array of cellular consequences such as activation of apoptotic pathways, generation of reactive oxygen species (ROS), cell cycle arrest and autophagy. Hence, there is a growing interest in the potential clinical use of HDAC inhibitors as a new class of targeted cancer therapeutics. Methodology and Result: Several research articles spanning between 2016 and 2017 were reviewed in this article and presently offer critical insights into the important strategies such as structure-based rational drug design, multi-parameter lead optimization methodologies, relevant SAR studies and biology of various class of HDAC inhibitors, such as hydroxamic acids, benzamides, cyclic peptides, aliphatic acids, summarising the clinical trials and results of various combination drug therapy till date. CONCLUSION This review will provide a platform to the synthetic chemists and biologists to cater the needs of both molecular targeted therapy and combination drug therapy to design and synthesize safe and selective HDAC inhibitors in cancer therapeutics.
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Affiliation(s)
- Faria Sultana
- Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500007, India
| | - Kesari Lakshmi Manasa
- Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500007, India.,Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Siddiq Pasha Shaik
- Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500007, India.,Academy of Scientific and Innovative Research, New Delhi, 110 025, India
| | - Srinivasa Reddy Bonam
- Vaccine Immunology Laboratory, Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
| | - Ahmed Kamal
- Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad-500007, India.,Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India.,Academy of Scientific and Innovative Research, New Delhi, 110 025, India.,School of Pharmaceutical Education and Research (SPER), Jamia Hamdard University, New Delhi, 110062, India
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35
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Sharma MC, Sharma S. Molecular modeling study of uracil-based hydroxamic acids-containing histone deacetylase inhibitors. ARAB J CHEM 2019. [DOI: 10.1016/j.arabjc.2014.12.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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36
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Yu N, Chen P, Wang Q, Liang M, Qiu J, Zhou P, Yang M, Yang P, Wu Y, Han X, Ge J, Zhuang J, Yu K. Histone deacetylase inhibitors differentially regulate c-Myc expression in retinoblastoma cells. Oncol Lett 2019; 19:460-468. [PMID: 31897159 PMCID: PMC6923973 DOI: 10.3892/ol.2019.11111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 10/22/2019] [Indexed: 12/15/2022] Open
Abstract
Retinoblastoma (RB) is the most prevalent childhood intraocular cancer type. Previous studies have demonstrated that c-myc (a proto-oncogene) is associated with tumorigenesis. However, at present, the influence of the expression profile and bioactivity of c-Myc on RB occurrence and progression is yet to be characterised. Notably, the present study demonstrated that c-myc is downregulated in the RB cell line WERI-Rb1. However, treatment with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) was revealed to significantly upregulate the expression of c-Myc mRNA and protein in WERI-Rb1 cells. Moreover, TSA increased the activity of the c-myc promoter in WERI-Rb1 cells, and the expression of c-Myc was also regulated by other HDAC inhibitors, including vorinostat (SAHA), valproic acid sodium salt (VPA) and entinostat. Notably, although c-myc was silenced in the Y79 cell line, the HDAC inhibitor TSA did not induce upregulation of mRNA and protein in Y79 cells. By contrast, certain HDAC inhibitors (TSA, VPA and SAHA) were discovered to significantly decrease the activity of the c-myc promoter in Y79 cells. Furthermore, the current data indicated that exogenous c-myc expression has a mild inhibitory effect on WERI-Rb1 and Y79 cell viability. Therefore, the present study revealed novel insights into the expression mechanism and bioactivity of c-Myc in RB cells.
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Affiliation(s)
- Na Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Pei Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Qiyun Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Meixin Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Jin Qiu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Pan Zhou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Meng Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Panyang Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Yihui Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Xiaokun Han
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Jian Ge
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Keming Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong 510060, P.R. China
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37
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Miceli M, Cutignano A, Conte M, Ummarino R, Romanelli A, Ruvo M, Leone M, Mercurio FA, Doti N, Manzo E, Romano G, Altucci L, Ianora A. Monoacylglycerides from the Diatom Skeletonema marinoi Induce Selective Cell Death in Cancer Cells. Mar Drugs 2019; 17:md17110625. [PMID: 31683792 PMCID: PMC6891494 DOI: 10.3390/md17110625] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/22/2019] [Accepted: 10/28/2019] [Indexed: 12/21/2022] Open
Abstract
Microalgae are an excellent source of valuable compounds for nutraceutical and cosmeceutical applications. These photosynthesizing microorganisms are amenable for large-scale production, thus overcoming the bottleneck of biomass supply for chemical and activity characterization of bioactive compounds. This characteristic has recently also prompted the screening of microalgae for potential pharmaceutical applications. Here, we show that monoacylglycerides (MAGs) purified from the marine diatom Skeletonema marinoi have selective cytotoxic activity against the haematological cancer cell line U-937 and colon cancer cell line HCT-116 compared to normal MePR-2B cells. LC-MS analysis of the raw extract revealed that in their natural form, MAGs occur as 2-monoacyl derivatives and include mainly C16 and C20 analogues, but they are converted into the corresponding 1-isomers during purification processes. Pure compounds along with the synthetic 1-monoarachidonoylglycerol tested on HCT-116 and U-937 tumor cell lines induced cell death via apoptosis. The mechanism of action was investigated, and we show that it involves the induction of apoptosis through caspase 3/7 activation. These findings pave the way for the possible use of these molecules as potential anticancer agents or as precursors for the generation of new and more potent and selective compounds against tumor cells.
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Affiliation(s)
- Marco Miceli
- CEINGE-Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy.
| | - Adele Cutignano
- CNR-Institute of Biomolecular Chemistry, Via Campi Flegrei 34, Pozzuoli, 80078 Naples, Italy.
| | - Mariarosaria Conte
- Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Raffaella Ummarino
- Institute of Biostructures and Bioimaging (IBB-CNR), Via Mezzocannone 16, 80134 Naples, Italy.
- Marine Biotechnology Department, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy.
| | - Alessandra Romanelli
- Department of Pharmaceutical Sciences, University of Milan, via Venezian 21, 20133 Milan, Italy.
| | - Menotti Ruvo
- Institute of Biostructures and Bioimaging (IBB-CNR), Via Mezzocannone 16, 80134 Naples, Italy.
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging (IBB-CNR), Via Mezzocannone 16, 80134 Naples, Italy.
| | - Flavia Anna Mercurio
- Institute of Biostructures and Bioimaging (IBB-CNR), Via Mezzocannone 16, 80134 Naples, Italy.
| | - Nunzianna Doti
- Institute of Biostructures and Bioimaging (IBB-CNR), Via Mezzocannone 16, 80134 Naples, Italy.
| | - Emiliano Manzo
- CNR-Institute of Biomolecular Chemistry, Via Campi Flegrei 34, Pozzuoli, 80078 Naples, Italy.
| | - Giovanna Romano
- Marine Biotechnology Department, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy.
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Adrianna Ianora
- Marine Biotechnology Department, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy.
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38
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Gambacorta V, Gnani D, Vago L, Di Micco R. Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects. Front Cell Dev Biol 2019; 7:207. [PMID: 31681756 PMCID: PMC6797914 DOI: 10.3389/fcell.2019.00207] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/11/2019] [Indexed: 12/19/2022] Open
Abstract
Over the past decades, our molecular understanding of acute myeloid leukemia (AML) pathogenesis dramatically increased, thanks also to the advent of next-generation sequencing (NGS) technologies. Many of these findings, however, have not yet translated into new prognostic markers or rationales for treatments. We now know that AML is a highly heterogeneous disease characterized by a very low mutational burden. Interestingly, the few mutations identified mainly reside in epigenetic regulators, which shape and define leukemic cell identity. In the light of these discoveries and given the increasing number of drugs targeting epigenetic regulators in clinical development and testing, great interest is emerging for the use of small molecules targeting leukemia epigenome. Together with their effects on leukemia cell-intrinsic properties, such as proliferation and survival, epigenetic drugs may affect the way leukemic cells communicate with the surrounding components of the tumor and immune microenvironment. Here, we review current knowledge on alterations in the AML epigenetic landscape and discuss the promises of epigenetic therapies for AML treatment. Finally, we summarize emerging molecular studies elucidating how epigenetic rewiring in cancer cells may as well exert immune-modulatory functions, boost the immune system, and potentially contribute to better patient outcomes.
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Affiliation(s)
- Valentina Gambacorta
- Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.,Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Milano-Bicocca University, Milan, Italy
| | - Daniela Gnani
- Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luca Vago
- Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Raffaella Di Micco
- Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
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39
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Buisman SC, de Haan G. Epigenetic Changes as a Target in Aging Haematopoietic Stem Cells and Age-Related Malignancies. Cells 2019; 8:E868. [PMID: 31405121 PMCID: PMC6721661 DOI: 10.3390/cells8080868] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 08/07/2019] [Accepted: 08/09/2019] [Indexed: 12/14/2022] Open
Abstract
Aging is associated with multiple molecular and functional changes in haematopoietic cells. Most notably, the self-renewal and differentiation potential of hematopoietic stem cells (HSCs) are compromised, resulting in myeloid skewing, reduced output of red blood cells and decreased generation of immune cells. These changes result in anaemia, increased susceptibility for infections and higher prevalence of haematopoietic malignancies. In HSCs, age-associated global epigenetic changes have been identified. These epigenetic alterations in aged HSCs can occur randomly (epigenetic drift) or are the result of somatic mutations in genes encoding for epigenetic proteins. Mutations in loci that encode epigenetic modifiers occur frequently in patients with haematological malignancies, but also in healthy elderly individuals at risk to develop these. It may be possible to pharmacologically intervene in the aberrant epigenetic program of derailed HSCs to enforce normal haematopoiesis or treat age-related haematopoietic diseases. Over the past decade our molecular understanding of epigenetic regulation has rapidly increased and drugs targeting epigenetic modifications are increasingly part of treatment protocols. The reversibility of epigenetic modifications renders these targets for novel therapeutics. In this review we provide an overview of epigenetic changes that occur in aging HSCs and age-related malignancies and discuss related epigenetic drugs.
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Affiliation(s)
- Sonja C Buisman
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9700 Groningen, The Netherlands.
| | - Gerald de Haan
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9700 Groningen, The Netherlands
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40
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Liang T, Hou X, Zhou Y, Yang X, Fang H. Design, Synthesis, and Biological Evaluation of 2,4-Imidazolinedione Derivatives as HDAC6 Isoform-Selective Inhibitors. ACS Med Chem Lett 2019; 10:1122-1127. [PMID: 31413795 DOI: 10.1021/acsmedchemlett.9b00084] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 07/05/2019] [Indexed: 01/23/2023] Open
Abstract
Histone deacetylase 6 (HDAC6) has emerged as a promising drug target for various human diseases, including diverse neurodegenerative diseases and cancer. Herein, we reported a series of 2,4-imidazolinedione derivatives as novel HDAC6 isoform-selective inhibitors based on structure-based drug design. Most target compounds exhibit good profiles in a preliminary screening concerning HDAC6 inhibitory activities. Moreover, the most active compound 10c increases the acetylation level of α-tubulin with little effect on the acetylation of histone H3. Further biological evaluation suggested that potent compound 10c, which possesses good antiproliferative activity, could induce apoptosis in HL-60 cell by activating caspase 3.
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Affiliation(s)
- Tao Liang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, P. R. China
| | - Xuben Hou
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, P. R. China
| | - Yi Zhou
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, P. R. China
| | - Xinying Yang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, P. R. China
| | - Hao Fang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, P. R. China
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41
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Li Y, Li Z, Zhu WG. Molecular Mechanisms of Epigenetic Regulators as Activatable Targets in Cancer Theranostics. Curr Med Chem 2019; 26:1328-1350. [PMID: 28933282 DOI: 10.2174/0929867324666170921101947] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 05/24/2017] [Accepted: 06/09/2017] [Indexed: 12/11/2022]
Abstract
Epigenetics is defined as somatically inheritable changes that are not accompanied by alterations in DNA sequence. Epigenetics encompasses DNA methylation, covalent histone modifications, non-coding RNA as well as nucleosome remodeling. Notably, abnormal epigenetic changes play a critical role in cancer development including malignant transformation, metastasis, prognosis, drug resistance and tumor recurrence, which can provide effective targets for cancer prognosis, diagnosis and therapy. Understanding these changes provide effective means for cancer diagnosis and druggable targets for better clinical applications. Histone modifications and related enzymes have been found to correlate well with cancer incidence and prognosis in recent years. Dysregulated expression or mutation of histone modification enzymes and histone modification status abnormalities have been considered to play essential roles in tumorigenesis and clinical outcomes of cancer treatment. Some of the histone modification inhibitors have been extensively employed in clinical practice and many others are still under laboratory research or pre-clinical assessment. Here we summarize the important roles of epigenetics, especially histone modifications in cancer diagnostics and therapeutics, and also discuss the developmental implications of activatable epigenetic targets in cancer theranostics.
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Affiliation(s)
- Yinglu Li
- Shenzhen University School of Medicine, Shenzhen 518060, China.,Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
| | - Zhiming Li
- Shenzhen University School of Medicine, Shenzhen 518060, China.,Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
| | - Wei-Guo Zhu
- Shenzhen University School of Medicine, Shenzhen 518060, China.,Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
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42
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Elmallah MIY, Micheau O. Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy. Cancers (Basel) 2019; 11:cancers11060850. [PMID: 31248188 PMCID: PMC6627638 DOI: 10.3390/cancers11060850] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/11/2019] [Accepted: 06/18/2019] [Indexed: 12/20/2022] Open
Abstract
One of the main characteristics of carcinogenesis relies on genetic alterations in DNA and epigenetic changes in histone and non-histone proteins. At the chromatin level, gene expression is tightly controlled by DNA methyl transferases, histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyl-binding proteins. In particular, the expression level and function of several tumor suppressor genes, or oncogenes such as c-Myc, p53 or TRAIL, have been found to be regulated by acetylation. For example, HATs are a group of enzymes, which are responsible for the acetylation of histone proteins, resulting in chromatin relaxation and transcriptional activation, whereas HDACs by deacetylating histones lead to chromatin compaction and the subsequent transcriptional repression of tumor suppressor genes. Direct acetylation of suppressor genes or oncogenes can affect their stability or function. Histone deacetylase inhibitors (HDACi) have thus been developed as a promising therapeutic target in oncology. While these inhibitors display anticancer properties in preclinical models, and despite the fact that some of them have been approved by the FDA, HDACi still have limited therapeutic efficacy in clinical terms. Nonetheless, combined with a wide range of structurally and functionally diverse chemical compounds or immune therapies, HDACi have been reported to work in synergy to induce tumor regression. In this review, the role of HDACs in cancer etiology and recent advances in the development of HDACi will be presented and put into perspective as potential drugs synergizing with TRAIL's pro-apoptotic potential.
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Affiliation(s)
- Mohammed I Y Elmallah
- INSERM, Université Bourgogne Franche-Comté, LNC UMR1231, F-21079 Dijon, France.
- Chemistry Department, Faculty of Science, Helwan University, Ain Helwan 11795 Cairo, Egypt.
| | - Olivier Micheau
- INSERM, Université Bourgogne Franche-Comté, LNC UMR1231, F-21079 Dijon, France.
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43
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Lawlor L, Yang XB. Harnessing the HDAC-histone deacetylase enzymes, inhibitors and how these can be utilised in tissue engineering. Int J Oral Sci 2019; 11:20. [PMID: 31201303 PMCID: PMC6572769 DOI: 10.1038/s41368-019-0053-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 05/02/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023] Open
Abstract
There are large knowledge gaps regarding how to control stem cells growth and differentiation. The limitations of currently available technologies, such as growth factors and/or gene therapies has led to the search of alternatives. We explore here how a cell's epigenome influences determination of cell type, and potential applications in tissue engineering. A prevalent epigenetic modification is the acetylation of DNA core histone proteins. Acetylation levels heavily influence gene transcription. Histone deacetylase (HDAC) enzymes can remove these acetyl groups, leading to the formation of a condensed and more transcriptionally silenced chromatin. Histone deacetylase inhibitors (HDACis) can inhibit these enzymes, resulting in the increased acetylation of histones, thereby affecting gene expression. There is strong evidence to suggest that HDACis can be utilised in stem cell therapies and tissue engineering, potentially providing novel tools to control stem cell fate. This review introduces the structure/function of HDAC enzymes and their links to different tissue types (specifically bone, cardiac, neural tissues), including the history, current status and future perspectives of using HDACis for stem cell research and tissue engineering, with particular attention paid to how different HDAC isoforms may be integral to this field.
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Affiliation(s)
- Liam Lawlor
- Department of Oral Biology, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK
- Doctoral Training Centre in Tissue Engineering and Regenerative Medicine, Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds, UK
| | - Xuebin B Yang
- Department of Oral Biology, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK.
- Doctoral Training Centre in Tissue Engineering and Regenerative Medicine, Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds, UK.
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Alsawalha M, Rao Bolla S, Kandakatla N, Srinivasadesikan V, Veeraraghavan VP, Surapaneni KM. Molecular docking and ADMET analysis of hydroxamic acids as HDAC2 inhibitors. Bioinformation 2019; 15:380-387. [PMID: 31312074 PMCID: PMC6614126 DOI: 10.6026/97320630015380] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 05/05/2019] [Indexed: 11/23/2022] Open
Abstract
Histone deacetylase (HDAC2) belongs to the hydrolase family and a promising target for cancers. We reported 96 hydroxamic compounds optimized using hydrogen-donors, hydrophobic and electron withdrawing groups followed by molecular docking studies. The optimized compounds show good LibDock score and H-bond interaction in the active site of HDAC2. We selected 20 compounds as the best HDAC2 inhibitors based on the LibDock score, binding energy and hydrogen bonding. ADMET predictions on these compounds show good absorption, BBB penetration and no liver toxicity. We subsequently report four compounds selected as best HDAC2 inhibitors based on the LibDock, binding energy, H-bonding and ADMET properties.
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Affiliation(s)
- Murad Alsawalha
- Department of Chemical and Process Engineering Technology, Jubail Industrial College (JIC), P.O. Box 10099, Jubail Industrial City 31961,Kingdom of Saudi Arabia
| | - Srinivasa Rao Bolla
- Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O.Box 2114,Dammam 31451, Kingdom of Saudi Arabia
| | - Naresh Kandakatla
- Department of Chemistry, Sathyabama University, Jeppiaar Nagar, Chennai - 600 119, Tamil Nadu, India, 600119
| | - Venkatesan Srinivasadesikan
- Department of Applied Chemistry, National Chiao Tung University, Hsinchu, 300, Taiwan
- 5Division of Chemistry,Department of Sciences and Humanities, Vignan's Foundation for Science, Technology and Research University, Vadlamudi, 522 213,Guntur, Andhra Pradesh, India
| | - Vishnu Priya Veeraraghavan
- 6Department of Biochemistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, 162, P. H. Road, Velappanchavadi, Chennai - 600 077, Tamil Nadu, India
| | - Krishna Mohan Surapaneni
- 7Department of Medical Biochemistry, College of Applied Medical Sciences in Jubail (CAMSJ), Imam Abdulrahman Bin Faisal University, Jubail Industrial City 35816, Kingdom
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Pallavi R, Mazzarella L, Pelicci PG. Advances in precision epigenetic treatment for acute promyelocytic leukemia. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2019. [DOI: 10.1080/23808993.2019.1612238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Rani Pallavi
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Luca Mazzarella
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Division of Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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46
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Fox CR, Parks GD. Histone Deacetylase Inhibitors Enhance Cell Killing and Block Interferon-Beta Synthesis Elicited by Infection with an Oncolytic Parainfluenza Virus. Viruses 2019; 11:E431. [PMID: 31083335 PMCID: PMC6563284 DOI: 10.3390/v11050431] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 12/28/2022] Open
Abstract
Previous results have shown that infection with the cytoplasmic-replicating parainfluenza virus 5 mutant P/V-CPI- sensitizes cells to DNA damaging agents, resulting in the enhanced killing of airway cancer cells. Here, we have tested the hypothesis that histone deacetylase (HDAC) inhibitors can also act with P/V-CPI- infection to enhance cancer cell killing. Using human small cell lung cancer and laryngeal cancer cell lines, 10 HDAC inhibitors were tested for their effect on viability of P/V-CPI- infected cells. HDAC inhibitors such as scriptaid enhanced caspase-3/7, -8 and -9 activity induced by P/V-CPI- and overall cell toxicity. Scriptaid-mediated enhanced killing was eliminated in lung cancer cells that were engineered to express a protein which sequesters double stranded RNA. Scriptaid also enhanced cancer cell killing by two other negative strand RNA viruses - the La Crosse virus and vesicular stomatitis virus. Scriptaid treatment enhanced the spread of the P/V-CPI- virus through a population of cancer cells, and suppressed interferon-beta induction through blocking phosphorylation and nuclear translocation of Interferon Regulatory Factor 3 (IRF-3). Taken together, these data support a role for combinations of a cytoplasmic-replicating RNA virus such as the P/V-CPI- mutant along with chemotherapeutic agents.
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Affiliation(s)
- Candace R Fox
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
| | - Griffith D Parks
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
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Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can initiate the apoptosis pathway by binding to its associated death receptors DR4 and DR5. The activation of the TRAIL pathway in inducing tumor-selective apoptosis leads to the development of TRAIL-based cancer therapies, which include recombinant forms of TRAIL, TRAIL receptor agonists, and other therapeutic agents. Importantly, TRAIL, DR4, and DR5 can all be induced by synthetic and natural agents that activate the TRAIL apoptosis pathway in cancer cells. Thus, understanding the regulation of the TRAIL apoptosis pathway can aid in the development of TRAIL-based therapies for the treatment of human cancer.
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48
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Yang J, He J, Ismail M, Tweeten S, Zeng F, Gao L, Ballinger S, Young M, Prabhu SD, Rowe GC, Zhang J, Zhou L, Xie M. HDAC inhibition induces autophagy and mitochondrial biogenesis to maintain mitochondrial homeostasis during cardiac ischemia/reperfusion injury. J Mol Cell Cardiol 2019; 130:36-48. [PMID: 30880250 PMCID: PMC6502701 DOI: 10.1016/j.yjmcc.2019.03.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 02/03/2019] [Accepted: 03/11/2019] [Indexed: 12/25/2022]
Abstract
AIMS The FDA-approved histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA, Vorinostat) has been shown to induce cardiomyocyte autophagy and blunt ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, the precise mechanisms underlying the cardioprotective activity of SAHA are unknown. Mitochondrial dysfunction and oxidative damage are major contributors to myocardial apoptosis during I/R injury. We hypothesize that SAHA protects the myocardium by maintaining mitochondrial homeostasis and reducing reactive oxygen species (ROS) production during I/R injury. METHODS Mouse and cultured cardiomyocytes (neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes) I/R models were used to investigate the effects of SAHA on mitochondria. ATG7 knockout mice, ATG7 knockdown by siRNA and PGC-1α knockdown by adenovirus in cardiomyocytes were used to test the dependency of autophagy and PGC-1α-mediated mitochondrial biogenesis respectively. RESULTS Intact and total mitochondrial DNA (mtDNA) content and mitochondrial mass were significantly increased in cardiomyocytes by SAHA pretreatment before simulated I/R. In vivo, I/R induced >50% loss of mtDNA content in the border zones of mouse hearts, but SAHA pretreatment and reperfusion treatment alone reverted mtDNA content and mitochondrial mass to control levels. Moreover, pretreatment of cardiomyocytes with SAHA resulted in a 4-fold decrease in I/R-induced loss of mitochondrial membrane potential and a 25%-40% reduction in cytosolic ROS levels. However, loss-of-function of ATG7 in cardiomyocytes or mouse myocardium abolished the protective effects of SAHA on ROS levels, mitochondrial membrane potential, mtDNA levels, and mitochondrial mass. Lastly, PGC-1α gene expression was induced by SAHA in NRVMs and mouse heart subjected to I/R, and loss of PGC-1α abrogated SAHA's mitochondrial protective effects in cardiomyocytes. CONCLUSIONS SAHA prevents I/R induced-mitochondrial dysfunction and loss, and reduces myocardial ROS production when given before or after the ischemia. The protective effects of SAHA on mitochondria are dependent on autophagy and PGC-1α-mediated mitochondrial biogenesis.
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Affiliation(s)
- Jing Yang
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Jin He
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Mahmoud Ismail
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Sonja Tweeten
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Fanfang Zeng
- Dept. of Cardiovascular Disease, Shenzhen Sun Yat-Sen Cardiovascular Hospital, 518020, China
| | - Ling Gao
- Dept. of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Scott Ballinger
- Dept. of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Martin Young
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Sumanth D Prabhu
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Glenn C Rowe
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Jianyi Zhang
- Dept. of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Lufang Zhou
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Min Xie
- Dept. of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America.
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Manzotti G, Ciarrocchi A, Sancisi V. Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy. Cancers (Basel) 2019; 11:cancers11030304. [PMID: 30841549 PMCID: PMC6468908 DOI: 10.3390/cancers11030304] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 02/18/2019] [Accepted: 02/26/2019] [Indexed: 12/14/2022] Open
Abstract
Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance.
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Affiliation(s)
- Gloria Manzotti
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy.
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy.
| | - Valentina Sancisi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy.
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Sah A, Sotnikov S, Kharitonova M, Schmuckermair C, Diepold RP, Landgraf R, Whittle N, Singewald N. Epigenetic Mechanisms Within the Cingulate Cortex Regulate Innate Anxiety-Like Behavior. Int J Neuropsychopharmacol 2019; 22:317-328. [PMID: 30668714 PMCID: PMC6441131 DOI: 10.1093/ijnp/pyz004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/11/2019] [Accepted: 01/14/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Pathological anxiety originates from a complex interplay of genetic predisposition and environmental factors, acting via epigenetic mechanisms. Epigenetic processes that can counteract detrimental genetic risk towards innate high anxiety are not well characterized. METHODS We used female mouse lines of selectively bred high (HAB)- vs low (LAB)-innate anxiety-related behavior and performed select environmental and pharmacological manipulations to alter anxiety levels as well as brain-specific manipulations and immunohistochemistry to investigate neuronal mechanisms associated with alterations in anxiety-related behavior. RESULTS Inborn hyperanxiety of high anxiety-like phenotypes was effectively reduced by environmental enrichment exposure. c-Fos mapping revealed that hyperanxiety in high anxiety-like phenotypes was associated with blunted challenge-induced neuronal activation in the cingulate-cortex, which was normalized by environmental enrichment. Relating this finding with epigenetic modifications, we found that high anxiety-like phenotypes (compared with low-innate anxiety phenotypes) showed reduced acetylation in the hypoactivated cingulate-cortex neurons following a mild emotional challenge, which again was normalized by environmental enrichment. Paralleling the findings using environmental enrichment, systemic administration of histone-deacetylase-inhibitor MS-275 elicited an anxiolytic-like effect, which was correlated with increased acetylated-histone-3 levels within cingulate-cortex. Finally, as a proof-of-principle, local MS-275 injection into cingulate-cortex rescued enhanced innate anxiety and increased acetylated-histone-3 within the cingulate-cortex, suggesting this epigenetic mark as a biomarker for treatment success. CONCLUSIONS Taken together, the present findings provide the first causal evidence that the attenuation of high innate anxiety-like behavior via environmental/pharmacological manipulations is epigenetically mediated via acetylation changes within the cingulate-cortex. Finally, histone-3 specific histone-deacetylase-inhibitor could be of therapeutic importance in anxiety disorders.
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Affiliation(s)
- Anupam Sah
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | | | - Maria Kharitonova
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Claudia Schmuckermair
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | | | | | - Nigel Whittle
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
| | - Nicolas Singewald
- Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria,Correspondence: Nicolas Singewald, PhD, Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80–82/III, A-6020 Innsbruck, Austria ()
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