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Nie S, Chang L, Huang Y, Zhou H, Yang Q, Kong L, Li Y. β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:3. [PMID: 38169019 PMCID: PMC10761647 DOI: 10.1007/s13659-023-00422-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 11/22/2023] [Indexed: 01/05/2024]
Abstract
Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.
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Affiliation(s)
- Shiyun Nie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Lizhong Chang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Ying Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Heyang Zhou
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Qianqing Yang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China
| | - Lingmei Kong
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
| | - Yan Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China.
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Chen Y, Chen M, Deng K. Blocking the Wnt/β‑catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review). Int J Oncol 2022; 62:24. [PMID: 36579676 PMCID: PMC9854240 DOI: 10.3892/ijo.2022.5472] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/02/2022] [Indexed: 12/28/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumor types occurring in the digestive system. The incidence of CRC has exhibits yearly increases and the mortality rate among patients with CRC is high. The Wnt/β‑catenin signaling pathway, which is associated with carcinogenesis, is abnormally activated in CRC. Most patients with CRC have adenomatous polyposis coli mutations, while half of the remaining patients have β‑catenin gene mutations. Therefore, targeting the Wnt/β‑catenin signaling pathway for the treatment of CRC is of clinical value. In recent years, with in‑depth research on the Wnt/β‑catenin signaling pathway, inhibitors have been developed that are able to suppress or hinder the development and progression of CRC. In the present review, the role of the Wnt/β‑catenin signaling pathway in CRC is summarized, the research status on Wnt/β‑catenin pathway inhibitors is outlined and potential targets for inhibition of this pathway are presented.
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Affiliation(s)
- Yuxiang Chen
- Department of Gastroenterology and Hepatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China,The Laboratory of Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Mo Chen
- Department of Gerontology, Tibetan Chengdu Branch Hospital of West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China,Department of Gerontology, Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region, Chengdu, Sichuan 610041, P.R. China,Professor Mo Chen, Department of Gerontology, Tibetan Chengdu Branch Hospital of West China Hospital, Sichuan University, 20 Ximianqiao Cross Street, Chengdu, Sichuan 610041, P.R. China, E-mail:
| | - Kai Deng
- Department of Gastroenterology and Hepatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China,The Laboratory of Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China,Correspondence to: Professor Kai Deng, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, P.R. China, E-mail:
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N,N-Bis(Substituted benzyl)-β-Carbolineum Bromides as Potential Anticancer Therapeutics: Design, Synthesis, Cytotoxicity, Drug-DNA Intercalation and In-Silico Binding Properties. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.130771] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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A comprehensive overview of β-carbolines and its derivatives as anticancer agents. Eur J Med Chem 2021; 224:113688. [PMID: 34332400 DOI: 10.1016/j.ejmech.2021.113688] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 05/05/2021] [Accepted: 07/04/2021] [Indexed: 01/13/2023]
Abstract
β-Carboline alkaloids are a family of natural and synthetic products with structural diversity and outstanding antitumor activities. This review summarizes research developments of β-carboline and its derivatives as anticancer agents, which focused on both natural and synthetic monomers as well as dimers. In addition, the structure-activity relationship (SAR) analysis of β-carboline monomers and dimers are summarized and mechanism of action of β-carboline and its derivatives are also presented. A few possible research directions, suggestions and clues for future work on the development of novel β-carboline-based anticancer agents with improved expected activities and lesser toxicity are also provided.
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Membrane dynamics in Leishmania amazonensis and antileishmanial activities of β-carboline derivatives. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183473. [PMID: 32937102 DOI: 10.1016/j.bbamem.2020.183473] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/04/2020] [Accepted: 09/07/2020] [Indexed: 01/18/2023]
Abstract
Two β-carboline compounds, 8i and 6d, demonstrated in vitro antileishmanial activity against Leishmania (L.) amazonensis promastigotes similar to that of miltefosine (MIL). Estimates of the membrane-water partition coefficient (KM/W) and the compound concentrations in the membrane (cm50) and aqueous phase (cw50) for half maximal inhibitory concentration were made. Whereas these biophysical parameters for 6d were not significantly different from those reported for MIL, 8i showed lower affinity for the parasite membrane (lower KM/W) and a lower concentration of the compound in the membrane required to inhibit the growth of the parasite (lower cm50). A 2-hour treatment of Leishmania promastigotes with the compounds 8i and 6d caused membrane rigidity in a concentration-dependent manner, as demonstrated by the electron paramagnetic resonance (EPR) technique and spin label method. This increased rigidity of the membrane was interpreted to be associated with the occurrence of cross-linking of oxidized cytoplasmic proteins to the parasite membrane skeleton. Importantly, the two β-carboline-oxazoline derivatives showed low hemolytic action, both in experiments with isolated red blood cells or with whole blood, denoting their great Leishmania/erythrocyte selectivity index. Using electron microscopy, changes in the membrane of both the amastigote and promastigote form of the parasite were confirmed, and it was demonstrated that compounds 8i and 6d decreased the number of amastigotes in infected murine macrophages. Furthermore, 8i and 6d were more toxic to the protozoa than to J774A.1 macrophages, with treated promastigotes exhibiting a decrease in cell volume, mitochondrial membrane potential depolarization, accumulation of lipid bodies, increased ROS production and changes in the cell cycle.
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Peters XQ, Malinga TH, Agoni C, Olotu FA, Soliman MES. Zoning in on Tankyrases: A Brief Review on the Past, Present and Prospective Studies. Anticancer Agents Med Chem 2019; 19:1920-1934. [PMID: 31648650 DOI: 10.2174/1871520619666191019114321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/29/2019] [Accepted: 07/17/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Tankyrases are known for their multifunctionalities within the poly(ADPribose) polymerases family and playing vital roles in various cellular processes which include the regulation of tumour suppressors. Tankyrases, which exist in two isoforms; Tankyrase 1 and 2, are highly homologous and an integral part of the Wnt β -catenin pathway that becomes overly dysregulated when hijacked by pro-carcinogenic machineries. METHODS In this review, we cover the distinct roles of the Tankyrase isoforms and their involvement in the disease pathogenesis. Also, we provide updates on experimentally and computationally derived antagonists of Tankyrase whilst highlighting the precedence of integrative computer-aided drug design methods towards the discovery of selective inhibitors. RESULTS Despite the high prospects embedded in the therapeutic targeting and blockade of Tankyrase isoforms, the inability of small molecule inhibitors to achieve selective targeting has remained a major setback, even until date. This explains numerous incessant drug design efforts geared towards the development of highly selective inhibitors of the respective Tankyrase isoforms since they mediate distinct aberrancies in disease progression. Therefore, considering the setbacks of conventional drug design methods, can computer-aided approaches actually save the day? CONCLUSION The implementation of computer-aided drug design techniques in Tankyrase research could help complement experimental methods and facilitate ligand/structure-based design and discovery of small molecule inhibitors with enhanced selectivity.
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Affiliation(s)
- Xylia Q Peters
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Thembeka H Malinga
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Clement Agoni
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Fisayo A Olotu
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
| | - Mahmoud E S Soliman
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa
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Ma H, Lian C, Song Y. Fibulin-2 inhibits development of gastric cancer by downregulating β-catenin. Oncol Lett 2019; 18:2799-2804. [PMID: 31452758 PMCID: PMC6676648 DOI: 10.3892/ol.2019.10599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 04/25/2019] [Indexed: 11/17/2022] Open
Abstract
The aim of the present study was to investigate the expression of fibulin-2 and β-catenin in gastric cancer tissues and the association to mutual regulation. Forty-nine cases of gastric cancer specimens obtained via surgical resection in the Pathology Department of Heping Hospital Affiliated to Changzhi Medical College from March 2013 to August 2017 were collected. The expression levels of fibulin-2 and β-catenin in 49 cases of gastric cancer and para-carcinoma tissues were detected via quantitative polymerase chain reaction and immunohistochemistry. The correlation of expression of fibulin-2 and β-catenin proteins in gastric cancer was detected via Spearman's analysis. The correlation of fibulin-2 and β-catenin protein expression with clinicopathological indexes of patients was also analyzed. Moreover, the fibulin-2 overexpression plasmid was constructed and transfected into human gastric cancer AGS and SGC-790 cell lines, so as to observe changes in β-catenin and its downstream indexes. Fibulin-2 messenger ribonucleic acid (mRNA) level in gastric cancer tissues was significantly lower than that in para-carcinoma tissues, while β-catenin mRNA level was significantly increased (P<0.05). The positive rate of fibulin-2 protein was 73.47% (36/49) in gastric cancer tissues and 16.33% (8/49) in para-carcinoma tissues, while that of β-catenin was 77.55% (38/49) in gastric cancer tissues and 28.57% (14/49) in para-carcinoma tissues, indicating that fibulin-2 protein is significantly deleted in gastric cancer tissues, and β-catenin protein is significantly upregulated (P<0.001). Fibulin-2 and β-catenin had a negative correlation (r=−0.361, P=0.003), but was closely correlated with the tumor size and lymph node metastasis (P<0.05). After overexpression of fibulin-2, expression of β-catenin, cyclin D1 and c-Myc protein was obviously downregulated (P<0.05). The tumor suppressor gene, fibulin-2, is significantly deleted in gastric cancer tissues, while β-catenin is remarkably enriched. Overexpression of fibulin-2 can inhibit the development of gastric cancer by downregulating β-catenin.
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Affiliation(s)
- Hongping Ma
- Department of Surgical Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Changhong Lian
- Department of Surgical Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Yingming Song
- Department of Surgical Oncology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
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Song J, Shu H, Zhang L, Xiong J. Long noncoding RNA GAS5 inhibits angiogenesis and metastasis of colorectal cancer through the Wnt/β-catenin signaling pathway. J Cell Biochem 2019; 120:6937-6951. [PMID: 30672001 DOI: 10.1002/jcb.27743] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 08/31/2018] [Indexed: 01/24/2023]
Abstract
OBJECTIVE Angiogenesis plays a key role in the tumorigenesis and progression of colorectal cancer (CRC). In this study, we investigated the effect of long noncoding RNA (lncRNA) GAS5 on the angiogenesis, invasion, and metastasis of CRC, and the involvement of the Wnt/β-catenin signaling pathway. METHODS CRC tissues and adjacent normal tissues were collected from 52 patients with CRC. GAS5 expression was determined in vivo and in vitro by real-time quantitative polymerase chain reaction (RT-qPCR). Then RT-qPCR and Western blot were used to identify expression of key genes of Wnt/β-catenin signaling pathway. CRC cells with lowest GAS5 expression were selected and subjected to si-GAS5, oe-GAS5, or XAV939 to validate the effect of GAS5 and Wnt/β-catenin signaling pathway on CRC cell activities. The activation of Wnt/β-catenin signaling pathway was determined in response to GAS5. Subcutaneous tumor growth and microvascular density were observed in nude mice, in which in vivo metastasis was observed following tail vein injection of CRC cells. RESULTS Initially, poor expression of GAS5 was observed in CRC tissues and cells. Upregulated GAS5 repressed CRC cell invasion and migration in vitro, as well as subcutaneous tumor growth, angiogenesis, and liver metastases in vivo. Furthermore, the Wnt/β-catenin signaling pathway was determined to be activated in CRC tissues and cells, while its activation was inhibited by GAS5. The Wnt/β-catenin signaling pathway promoted the CRC cell invasion and migration in vitro, subcutaneous tumor growth, angiogenesis and, liver metastases in vivo. CONCLUSION Taken together, the results of the study conclude that lncRNA GAS5 inhibited the activation of the Wnt/β-catenin signaling pathway, thereby suppressing the angiogenesis, invasion, and metastasis of CRC.
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Affiliation(s)
- Jianping Song
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Department of Oncology, The Third Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongchun Shu
- Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Department of Gastroenterology, Shangrao People's Hospital, Shangrao, China
| | - Ling Zhang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Ji D, Zhan T, Li M, Yao Y, Jia J, Yi H, Qiao M, Xia J, Zhang Z, Ding H, Song C, Han Y, Gu J. Enhancement of Sensitivity to Chemo/Radiation Therapy by Using miR-15b against DCLK1 in Colorectal Cancer. Stem Cell Reports 2018; 11:1506-1522. [PMID: 30449704 PMCID: PMC6294114 DOI: 10.1016/j.stemcr.2018.10.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/19/2022] Open
Abstract
Chemo-/radiotherapy resistance is the main cause accounting for most treatment failure in colorectal cancer (CRC). Tumor-initiating cells (TICs) are the culprit leading to CRC chemo-/radiotherapy resistance. The underlying regulation mechanism of TICs in CRC remains unclear. Here we discovered that miR-15b expression positively correlated with therapeutic outcome in CRC. Expression of miR-15b in pretreatment biopsy tissue samples predicted tumor regression grade (TRG) in rectal cancer patients after receiving neoadjuvant radiotherapy (nRT). Expression of miR-15b in post-nRT tissue samples was associated with therapeutic outcome. DCLK1 was identified as the direct target gene for miR-15b and its suppression was associated with self-renewal and tumorigenic properties of DCLK1+ TICs. We identified B lymphoma Mo-MLV insertion region l homolog (BMI1) as a downstream target regulated by miR-15b/DCLK1 signaling. Thus, miR-15b may serve as a valuable marker for prognosis and therapeutic outcome prediction. DCLK1 could be a potential therapeutic target to overcome chemo-/radioresistance in CRC.
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Affiliation(s)
- Dengbo Ji
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Tiancheng Zhan
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Ming Li
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Yunfeng Yao
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Jinying Jia
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Haizhao Yi
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Meng Qiao
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Jinhong Xia
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Zhiqian Zhang
- Department of Cell Biology, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Huirong Ding
- Central Laboratory, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Can Song
- School of Life Sciences, Tsinghua University, Beijing 100084, China; Peking-Tsinghua Center for Life Sciences, Beijing 100084, China
| | - Yong Han
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China
| | - Jin Gu
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China; Peking-Tsinghua Center for Life Sciences, Beijing 100084, China; Peking University S.G. Hospital, Beijing 100144, China.
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Tiwari A, Saraf S, Verma A, Panda PK, Jain SK. Novel targeting approaches and signaling pathways of colorectal cancer: An insight. World J Gastroenterol 2018; 24:4428-4435. [PMID: 30357011 PMCID: PMC6196338 DOI: 10.3748/wjg.v24.i39.4428] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/24/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog (SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC. Targeted therapies necessitate information regarding the particular aberrant pathways. Advancements in gene therapies have resulted in the recognition of novel therapeutic targets related with these signal-transduction cascades. CRC is a step-wise process where mutations occur over the time and activation of oncogenes and deactivation of tissue suppressor genes takes place. Genetic changes which are responsible for the induction of carcinogenesis include loss of heterozygosity in tumor suppressor genes such as adenomatous polyposis coli, mutation or deletion of genes like p53 and K-ras. Therefore, many gene-therapy approaches like gene correction, virus-directed enzyme-prodrug therapy, immunogenetic manipulation and virotherapy are currently being explored. Development of novel strategies for the safe and effective delivery of drugs to the cancerous site is the need of the hour. This editorial accentuates different novel strategies with emphasis on gene therapy and immunotherapy for the management of CRC.
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Affiliation(s)
- Ankita Tiwari
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Shivani Saraf
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Amit Verma
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Pritish Kumar Panda
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Sanjay K Jain
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
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Tokala R, Thatikonda S, Vanteddu US, Sana S, Godugu C, Shankaraiah N. Design and Synthesis of DNA-Interactive β-Carboline-Oxindole Hybrids as Cytotoxic and Apoptosis-Inducing Agents. ChemMedChem 2018; 13:1909-1922. [DOI: 10.1002/cmdc.201800402] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Ramya Tokala
- Department of Medicinal Chemistry; National Institute of Pharmaceutical Education and Research (NIPER); Hyderabad 500037 India
| | - Sowjanya Thatikonda
- Department of Regulatory Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Hyderabad 500037 India
| | - Usha Sree Vanteddu
- Department of Medicinal Chemistry; National Institute of Pharmaceutical Education and Research (NIPER); Hyderabad 500037 India
| | - Sravani Sana
- Department of Medicinal Chemistry; National Institute of Pharmaceutical Education and Research (NIPER); Hyderabad 500037 India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology; National Institute of Pharmaceutical Education and Research (NIPER); Hyderabad 500037 India
| | - Nagula Shankaraiah
- Department of Medicinal Chemistry; National Institute of Pharmaceutical Education and Research (NIPER); Hyderabad 500037 India
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13
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Qin JJ, Wang W, Li X, Deokar H, Buolamwini JK, Zhang R. Inhibiting β-Catenin by β-Carboline-Type MDM2 Inhibitor for Pancreatic Cancer Therapy. Front Pharmacol 2018; 9:5. [PMID: 29387014 PMCID: PMC5776119 DOI: 10.3389/fphar.2018.00005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 01/03/2018] [Indexed: 01/24/2023] Open
Abstract
The β-catenin and MDM2 oncoproteins are overexpressed and constitutively activated in human pancreatic cancer and contribute to its initiation, progression, and metastasis. The Wnt/β-catenin signaling pathway strongly interacts with the MDM2-p53 signaling pathway, accelerating the tumorigenesis and its development. Therefore, therapies inhibiting both β-catenin and MDM2 are suggested to be ideal treatments for patients with advanced pancreatic cancer. We have recently identified a novel class of β-carboline compounds as the specific and potent MDM2 inhibitors, including a lead compound SP141. In the present study, we utilized SP141 as an exemplary β-carboline compound to characterize β-catenin as a molecular target of the β-carboline compounds and to demonstrate an important role of β-catenin in the anticancer activity of β-carboline. We found that the silencing of either β-catenin or MDM2 largely reduced the anticancer activity of SP141 while the double silencing of both genes almost completely blocked SP141’s activity. SP141 directly bound to β-catenin and inhibited its expression and activity in pancreatic cancer cells in vitro and in vivo. The inhibitory effects of SP141 on β-catenin were mediated by the ubiquitin–proteasome system in an MDM2-independent manner. In conclusion, these results suggest that SP141 exerts its anticancer activity by dually inhibiting β-catenin and MDM2. We envision that β-carboline derivatives can be developed as promising dual inhibitors of β-catenin and MDM2 for the treatment of advanced pancreatic cancer.
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Affiliation(s)
- Jiang-Jiang Qin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
| | - Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States.,Center for Drug Discovery, University of Houston, Houston, TX, United States
| | - Xin Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
| | - Hemantkumar Deokar
- Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - John K Buolamwini
- Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States.,Center for Drug Discovery, University of Houston, Houston, TX, United States
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Tokala R, Thatikonda S, Sana S, Regur P, Godugu C, Shankaraiah N. Synthesis and in vitro cytotoxicity evaluation of β-carboline-linked 2,4-thiazolidinedione hybrids: potential DNA intercalation and apoptosis-inducing studies. NEW J CHEM 2018. [DOI: 10.1039/c8nj03248c] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A series of β-carboline-linked 2,4-thiazolidinedione hybrids was synthesized and studied for their DNA affinities and cytotoxicities. The most potent compound was 19e with IC50 of 0.97 ± 0.13 μM.
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Affiliation(s)
- Ramya Tokala
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER)
- Hyderabad-500037
- India
| | - Sowjanya Thatikonda
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)
- Hyderabad-500037
- India
| | - Sravani Sana
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER)
- Hyderabad-500037
- India
| | | | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)
- Hyderabad-500037
- India
| | - Nagula Shankaraiah
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER)
- Hyderabad-500037
- India
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15
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Bayraktar O, Ozkirimli E, Ulgen K. Sphingosine kinase 1 (SK1) allosteric inhibitors that target the dimerization site. Comput Biol Chem 2017; 69:64-76. [PMID: 28587987 DOI: 10.1016/j.compbiolchem.2017.05.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 01/29/2017] [Accepted: 05/24/2017] [Indexed: 02/03/2023]
Abstract
The sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) signaling pathway is a crucial target for numerous human diseases from cancer to cardiovascular diseases. However, available SK1 inhibitors that target the active site suffer from poor potency, selectivity and pharmacokinetic properties. The selectivity issue of the kinases, which share a highly-conserved ATP-pocket, can be overcome by targeting the less-conserved allosteric sites. SK1 is known to function minimally as a dimer; however, the crystal structure of the SK1 dimer has not been determined. In this study, a template-based algorithm implemented in PRISM was used to predict the SK1 dimer structure and then the possible allosteric sites at the dimer interface were determined via SiteMap. These sites were used in a virtual screening campaign that includes an integrated workflow of structure-based pharmacophore modeling, virtual screening, molecular docking, re-screening of common scaffolds to propose a series of compounds with different scaffolds as potential allosteric SK1 inhibitors. Finally, the stability of the SK1-ligand complexes was analyzed by molecular dynamics simulations. As a final outcome, ligand 7 having a 4,9-dihydro-1H-purine scaffold and ligand 12 having a 2,3,4,9-tetrahydro-1H-β-carboline scaffold were found to be potential selective inhibitors for SK1.
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Affiliation(s)
- Ozge Bayraktar
- Department of Computational Science and Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey
| | - Elif Ozkirimli
- Department of Computational Science and Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey; Department of Chemical Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey.
| | - Kutlu Ulgen
- Department of Computational Science and Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey; Department of Chemical Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey.
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16
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Yang TW, Gao YH, Ma SY, Wu Q, Li ZF. Low-grade slightly elevated and polypoid colorectal adenomas display differential β-catenin-TCF/LEF activity, c-Myc, and cyclin D1 expression. World J Gastroenterol 2017; 23:3066-3076. [PMID: 28533663 PMCID: PMC5423043 DOI: 10.3748/wjg.v23.i17.3066] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 12/07/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To comparatively investigate the cellular and molecular characteristics of low-grade slightly elevated adenomas and polypoid adenomas.
METHODS Colorectal tumors were collected from 24 patients with slightly elevated adenomas and 23 patients with polypoid adenomas. Five commonly mutated genes (APC, BRAF, KRAS, NRAS, and PIK3CA) were selected for mutational analysis. Paraffin-embedded tumor sections were used to calculate the apoptotic index (AI) and Ki-67 labeling index (KLI). Two pure colorectal epithelial cell lines were created by pooling the slightly elevated and polypoid tumors. Western blots, luciferase assays for β-catenin-T-cell factor protein/β-catenin-lymphoid enhancer factor (β-catenin-TCF/LEF)-driven transcriptional activity, and caspase activity assays were conducted on the two cell lines.
RESULTS Slightly elevated lesions showed a significantly lower APC mutational frequency and a significantly higher KRAS mutational frequency (both P < 0.05). Slightly elevated lesions showed a significantly lower AI (P < 0.05). β-catenin and β-catenin-TCF/LEF-driven transcriptional activity was significantly upregulated in slightly elevated lesions (both P < 0.05). In slightly elevated lesions, c-Myc was significantly downregulated, while cyclin D1 was significantly upregulated (both P < 0.05). β-catenin-TCF/LEF-driven transcriptional activity was negatively correlated with c-Myc (ρ = -0.78). Slightly elevated lesions displayed significant Bcl-2 and Bcl-xL upregulation (both P < 0.05) along with significant decreases in caspase-9 and caspase-3 activity (both P < 0.05). c-Myc was negatively correlated with Bcl-2 and Bcl-xL (ρ = -0.74 and -0.78, respectively).
CONCLUSION The lower apoptotic activity of low-grade slightly elevated adenomas can be partly attributed to upregulated β-catenin pathway activity and downregulated c-Myc expression.
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17
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Star-PAP, a poly(A) polymerase, functions as a tumor suppressor in an orthotopic human breast cancer model. Cell Death Dis 2017; 8:e2582. [PMID: 28151486 PMCID: PMC5386448 DOI: 10.1038/cddis.2016.199] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 06/03/2016] [Accepted: 06/08/2016] [Indexed: 12/21/2022]
Abstract
Star-PAP is a noncanonical poly(A) polymerase and required for the expression of a select set of mRNAs. However, the pathological role of Star-PAP in cancer largely remains unknown. In this study, we observed decreased expression of Star-PAP in breast cancer cell lines and tissues. Ectopic Star-PAP expression inhibited proliferation as well as colony-forming ability of breast cancer cells. In breast cancer patients, high levels of Star-PAP correlated with an improved prognosis. Moreover, by regulating the expression of BIK (BCL2-interacting killer), Star-PAP induced apoptosis of breast cancer cells through the mitochondrial pathway. The growth of breast cancer xenografts in NOD/SCID mice was also inhibited by the doxycycline-induced Star-PAP overexpression. Furthermore, Star-PAP sensitized breast cancer cells to chemotherapy drugs both in vitro and in vivo. In mammary epithelial cells, Star-PAP knockdown partially transformed these cells and induced them to undergo epithelial-mesenchymal transition (EMT). These findings suggested that Star-PAP possesses tumor-suppressing activity and can be a valuable target for developing new cancer therapeutic strategies.
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18
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Dighe SU, Yadav VD, Mahar R, Shukla SK, Batra S. Intramolecular Csp2–Csp2 Friedel–Crafts Arylation: Substrate- and Condition-Controlled Divergent Synthesis of Fused-β-carbolines. Org Lett 2016; 18:6010-6013. [DOI: 10.1021/acs.orglett.6b02794] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
| | | | | | | | - Sanjay Batra
- Academy of Scientific
and Innovative Research, New Delhi-110025, India
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19
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Affiliation(s)
- L Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - B Mao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - H Zhu
- Chinese Center for Chirality, Key Laboratory of Medicinal Chemistry and Molecular Diagnostics of Education Committee of China, Hebei University, Baoding 071002, China
| | - Y Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
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