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Jeong GH, Lee H, Cho JY, Rho JR, Chung BY, Park S, Bai HW. Isoquinocycline B induces G0/G1 cell cycle arrest and apoptosis in MDA-MB-231 cancer cells. Bioorg Med Chem Lett 2025; 124:130244. [PMID: 40254075 DOI: 10.1016/j.bmcl.2025.130244] [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: 02/04/2025] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
Breast cancer remains one of the leading causes of cancer-related deaths, with therapeutic resistance and limited treatment options posing significant challenges. This study investigated the anticancer properties of isoquinocycline B (IQCB), an anthraquinone derivative obtained from a freshwater sponge microbiome Micromonospora sp. MS-62 (FBCC-B8445), against the MDA-MB-231 human breast cancer cell line. IQCB showed the greatest activity against cytotoxicity with an IC50 values of 9.2 ± 1.0 μM. IQCB treatment led to G0/G1 cell cycle arrest and apoptosis through mitochondrial pathways by suppressing cyclin D1/CDK4 expression, enhancing p27 levels, and reducing phosphorylated Akt levels. Furthermore, IQCB induced oxidative stress by promoting excessive reactive oxygen species (ROS) production, thereby activating JNK and p38-MAPK signaling while simultaneously inhibiting ERK phosphorylation. Apoptotic markers such as PARP cleavage and caspase-3 activation confirmed that mitochondrial-mediated apoptosis was a key mechanism of action. These results highlight the potential of IQCB as a therapeutic candidate for breast cancer and underscore the need for further research to explore its efficacy and mechanisms.
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Affiliation(s)
- Gyeong Han Jeong
- Research division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI), Jeongeup 56212, Republic of Korea
| | - Hanui Lee
- Research division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI), Jeongeup 56212, Republic of Korea
| | - Ja Young Cho
- Prokaryote Research Division, Nakdonggang National Institute of Biological Resources (NNIBR), Sangju, 37242, Republic of Korea
| | - Jung-Rae Rho
- Department of Oceanography, Kunsan National University, Gunsan 54150, Republic of Korea
| | - Byung Yeoup Chung
- Research division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI), Jeongeup 56212, Republic of Korea
| | - Sanghwa Park
- Bio-resources Bank Division, Nakdonggang National Institute of Biological Resources (NNIBR), Sangju, 37242, Republic of Korea.
| | - Hyoung-Woo Bai
- Research division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI), Jeongeup 56212, Republic of Korea; Radiation Biotechnology and Applied Radioisotope Science, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
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Song W, Zhang H, Ni J, Hu H, Mao W, Wang K, Peng B. ALKBH5 promotes malignant proliferation of renal clear cell carcinoma by activating the MAPK pathway through binding to HNRNPDL. Int Immunopharmacol 2025; 145:113776. [PMID: 39657539 DOI: 10.1016/j.intimp.2024.113776] [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: 08/20/2024] [Revised: 11/23/2024] [Accepted: 12/01/2024] [Indexed: 12/12/2024]
Abstract
It is well established that ALKBH5 plays a crucial role in the malignant progression of various types of tumors. However, its role in clear cell renal cell carcinoma (ccRCC) and the underlying regulatory mechanisms remain unclear. In this study, we employed a range of techniques, including protein blotting, real-time quantitative PCR, silver staining, mass spectrometry, co-immunoprecipitation (Co-IP), GST-pull down, and immunofluorescence, to investigate the functions of ALKBH5 in ccRCC and elucidate the specific mechanisms involved. Our results demonstrated that ALKBH5 expression was significantly upregulated in ccRCC. In vitro experiments revealed that ALKBH5 promoted tumor proliferation, invasion, migration, and stemness. In vivo, ALKBH5 was shown to enhance tumor growth and lung metastasis. Mechanistically, our studies suggest that ALKBH5 accelerates the malignant progression of ccRCC by binding to heterogeneous nuclear ribonucleoprotein D-like (HNRNPDL), facilitating the nuclear translocation of MEK, ERK, and p38, and activating downstream targets such as c-Myc and PCNA.
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Affiliation(s)
- Wei Song
- Department of Urology, Shanghai Putuo District People's Hospital, School of Medicine, Tongji University, 1291 Jiangning Road, Pu'tuo District, Shanghai 200060, China; Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No. 301, Yanchang Middle Road, 200072 Shanghai, China
| | - Houliang Zhang
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing 210009, China
| | - Jinliang Ni
- Department of Urology, Shanghai Putuo District People's Hospital, School of Medicine, Tongji University, 1291 Jiangning Road, Pu'tuo District, Shanghai 200060, China; Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No. 301, Yanchang Middle Road, 200072 Shanghai, China
| | - Huiqing Hu
- Department of Ultrasound, The Sixth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Weipu Mao
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, No. 87 Dingjiaqiao, Hunan Road, Gulou District, Nanjing 210009, China.
| | - Keyi Wang
- Department of Urology, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai 200032, China.
| | - Bo Peng
- Department of Urology, Shanghai Putuo District People's Hospital, School of Medicine, Tongji University, 1291 Jiangning Road, Pu'tuo District, Shanghai 200060, China; Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No. 301, Yanchang Middle Road, 200072 Shanghai, China.
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Suryavanshi A, Vandana, Shukla YK, Kumar V, Gupta P, Asati V, Mahapatra DK, Keservani RK, Jain SK, Bharti SK. MEK inhibitors in oncology: a patent review and update (2016 - present). Expert Opin Ther Pat 2024; 34:963-1007. [PMID: 39275922 DOI: 10.1080/13543776.2024.2403634] [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: 05/15/2024] [Revised: 07/12/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024]
Abstract
INTRODUCTION Mitogen-activated protein kinase (MEK) is one of the important components of Ras/Raf/MEK/ERK signaling pathway, transduces signal for cell growth, differentiation, and development. Deregulation of MEK leads to a wide variety of cancer; hence, MEK is considered as potential therapeutic targets for the treatment of cancer. The MEK1/2 inhibitors in combination with other inhibitors showed better therapeutic outcomes in various malignancies including resistant or relapsed or refractory cancer. AREAS COVERED A comprehensive patent literature from the year 2016 to May 2024 on MEK inhibitors in oncology, their combination products and structural insights have been reviewed through searching relevant information in PubMed, Scopus, Espacenet, Web of Science, World Intellectual Property Organization and Google Patent databases. EXPERT OPINION Overexpression and mutation of MEK have been reported to cause a wide variety of cancers especially resistant cancers. The MEK1/2 inhibitors in combination with other kinase (BRaf/KRas/PI3K) inhibitors showed significant anti-proliferative activity. Other combination of MEK inhibitor with PD-1, DYRK1, EGFR, BTK and/or VEGF inhibitors, etc. showed promising results in many cancers including colorectal, pancreatic, gastrointestinal, solid tumor, breast cancer, melanoma and multiple myeloma, etc. The dual or multi-targeted approaches of these combinations showed better and precise treatment of patients with resistant cancer.
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Affiliation(s)
- Anjali Suryavanshi
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Vandana
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Yugal Kishor Shukla
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Vipul Kumar
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Pragya Gupta
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Vivek Asati
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Debarshi Kar Mahapatra
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Raj K Keservani
- Faculty of B. Pharmacy, CSM Group of Institutions, Prayagraj, India
| | - Sanmati Kumar Jain
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
| | - Sanjay Kumar Bharti
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India
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Fang RY, Liu YW, Goan YG, Lin JJ, Su JH, Wu WT, Wu YJ. Suppression of Migration and Invasion by 4-Carbomethoxyl-10-Epigyrosanoldie E from the Cultured Soft Coral Sinularia sandensis through the MAPKs Pathway on Oral Cancer Cells. Adv Pharmacol Pharm Sci 2024; 2024:6695837. [PMID: 38374934 PMCID: PMC10876307 DOI: 10.1155/2024/6695837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 12/27/2023] [Accepted: 01/20/2024] [Indexed: 02/21/2024] Open
Abstract
The primary reason for cancer-related fatalities is metastasis. The compound 4-carbomethoxyl-10-epigyrosanoldie E, derived from the Sinularia sandensis soft coral species grown in cultures, exhibits properties that counteract inflammation. Moreover, it has been observed to trigger both apoptosis and autophagy within cancerous cells. This research focuses on examining the inhibitory impact of 4-carbomethoxyl-10-epigyrosanoldie E on the migration and invasion processes in Cal-27 and Ca9-22 oral cancer cell lines. To assess how this compound affects cell migration and invasion, the Boyden chamber assay was employed. Furthermore, Western blot analysis was utilized to explore the underlying molecular mechanisms. In a dose-dependent manner, 4-carbomethoxyl-10-epigyrosanoldie E notably decreased the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9, along with urokinase-type plasminogen activator (uPA), in both Cal-27 and Ca9-22 cell lines. Conversely, it elevated the concentrations of tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2. In addition, the treatment with this compound led to the inhibition of phosphorylation in extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). It also curtailed the expression of several key proteins including focal adhesion kinase (FAK), protein kinase C (PKC), growth factor receptor-bound protein 2 (GRB2), Rac, Ras, Rho A, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and mitogen-activated protein kinase kinase 7 (MKK7). Furthermore, the expression levels of IQ-domain GTPase-activating protein 1 (IQGAP1) and zonula occludens-1 (ZO-1) were significantly reduced by the compound. The ability of 4-carbomethoxyl-10-epigyrosanoldie E to inhibit the migration and invasion of Cal-27 and Ca9-22 oral cancer cells was observed to be dose dependent. This inhibitory effect is primarily attributed to the suppression of MMP-2 and MMP-9 expression, as well as the downregulation of the mitogen-activated protein kinase (MAPK) signaling pathway.
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Affiliation(s)
- Rou-Yi Fang
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Pingtung Branch, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Yueh-Wen Liu
- Department of Cosmetics and Fashion Styling, Cheng Shiu University, Kaohsiung, Taiwan
| | - Yih-Gang Goan
- Division of Thoracic Surgery Department of Surgery, Pingtung Veterans General Hospital, Pingtung, Taiwan
| | - Jen-Jie Lin
- Yu Jun Biotechnology Co., Ltd., Kaohsiung, Taiwan
| | - Jui-Hsin Su
- National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan
| | - Wen-Tung Wu
- Department of Food Science and Nutrition, Meiho University, Pingtung 91202, Taiwan
| | - Yu-Jen Wu
- Yu Jun Biotechnology Co., Ltd., Kaohsiung, Taiwan
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Ram T, Singh AK, Kumar A, Singh H, Pathak P, Grishina M, Khalilullah H, Jaremko M, Emwas AH, Verma A, Kumar P. MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives. RSC Med Chem 2023; 14:1837-1857. [PMID: 37859720 PMCID: PMC10583825 DOI: 10.1039/d3md00145h] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/12/2023] [Indexed: 10/21/2023] Open
Abstract
MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the αC-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition.
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Affiliation(s)
- Teja Ram
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Harshwardhan Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
| | - Prateek Pathak
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University Chelyabinsk 454008 Russia
- Pharmaceutical Analysis and Quality Assurance and Pharmaceutical Chemistry, GITAM School of Pharmacy at "Hyderabad Campus", GITAM (Deemed to be University) India
| | - Maria Grishina
- Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University Chelyabinsk 454008 Russia
| | - Habibullah Khalilullah
- Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy, Qassim University Unayzah 51911 Saudi Arabia
| | - Mariusz Jaremko
- Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Abdul-Hamid Emwas
- Core Labs, King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia
| | - Amita Verma
- Bioorganic and Med. Chem. Res., Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences Prayagraj 211007 India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab Ghudda Bathinda 151401 India
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Lin TS, Huang WN, Yang JL, Peng SF, Liu KC, Chen JC, Hsia TC, Huang AC. Allyl isothiocyanate inhibits cell migration and invasion in human gastric cancer AGS cells via affecting PI3K/AKT and MAPK signaling pathway in vitro. ENVIRONMENTAL TOXICOLOGY 2023; 38:2287-2297. [PMID: 37318315 DOI: 10.1002/tox.23864] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 06/16/2023]
Abstract
Metastasis is commonly occurred in gastric cancer, and it is caused and responsible for one of the major cancer-related mortality in gastric cancer patients. Allyl isothiocyanate (AITC), a natural product, exhibits anticancer activities in human many cancer cells, including gastric cancer. However, no available report shows AITC inhibits gastric cancer cell metastasis. Herein, we evaluated the impact of AITC on cell migration and invasion of human gastric cancer AGS cells in vitro. AITC at 5-20 μM did not induce significant cell morphological damages observed by contrast-phase microscopy but decreased cell viability assayed by flow cytometry. After AGS cells were further examined by atomic force microscopy (AFM), which indicated AITC affected cell membrane and morphology in AGS cells. AITC significantly suppressed cell motility examined by scratch wound healing assay. The results of the gelatin zymography assay revealed that AITC significantly suppressed the MMP-2 and MMP-9 activities. In addition, AITC suppressed cell migration and invasion were performed by transwell chamber assays at 24 h in AGS cells. Furthermore, AITC inhibited cell migration and invasion by affecting PI3K/AKT and MAPK signaling pathways in AGS cells. The decreased expressions of p-AKTThr308 , GRB2, and Vimentin in AGS cells also were confirmed by confocal laser microscopy. Our findings suggest that AITC may be an anti-metastasis candidate for human gastric cancer treatment.
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Affiliation(s)
- Tzu-Shun Lin
- Department of Pharmacy, Saint Mary's Hospital Luodong, Luodong, Yilan, Taiwan
- Department of Nursing, Saint Mary's Junior College of Medicine, Nursing and Management, Sanxing, Yilan, Taiwan
| | - Wan-Nei Huang
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Jiun-Long Yang
- Department of Nursing, Saint Mary's Junior College of Medicine, Nursing and Management, Sanxing, Yilan, Taiwan
| | - Shu-Fen Peng
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Kuo-Ching Liu
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Jaw-Chyun Chen
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua, Taiwan
| | - Te-Chun Hsia
- Department of Respiratory Therapy, China Medical University, Taichung, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - An-Cheng Huang
- Department of Nursing, Saint Mary's Junior College of Medicine, Nursing and Management, Sanxing, Yilan, Taiwan
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Mukherjee O, Rakshit S, Shanmugam G, Sarkar K. Role of chemotherapeutic drugs in immunomodulation of cancer. CURRENT RESEARCH IN IMMUNOLOGY 2023; 4:100068. [PMID: 37692091 PMCID: PMC10491645 DOI: 10.1016/j.crimmu.2023.100068] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023] Open
Abstract
The immune system has a variety of potential effects on a tumor microenvironment and the course of chemotherapy may vary according to that. Anticancer treatments can encourage the release of unwanted signals from senescent tumor cells or the removal of immune-suppressive cells, which can lead to immune system activation. Hence, by inducing an immunological response and conversely making cancer cells more vulnerable to immune attack, chemotherapeutic agents can destroy cancer cells. Furthermore, chemotherapy can activate anticancer immune effectors directly or indirectly by thwarting immunosuppressive pathways. Therefore, in this review, we discuss how chemotherapeutic agents take part in immunomodulation and the molecular mechanisms underlying them. We also focus on the importance of carefully addressing the conflicting effects of chemotherapy on immune responses when developing successful combination treatments based on chemotherapy and immune modulators.
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Affiliation(s)
- Oishi Mukherjee
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Sudeshna Rakshit
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Geetha Shanmugam
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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Anticancer and Anti-Metastatic Role of Thymoquinone: Regulation of Oncogenic Signaling Cascades by Thymoquinone. Int J Mol Sci 2022; 23:ijms23116311. [PMID: 35682990 PMCID: PMC9181073 DOI: 10.3390/ijms23116311] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 12/04/2022] Open
Abstract
Cancer is a life-threatening and multifaceted disease. Pioneering research works in the past three decades have mechanistically disentangled intertwined signaling networks which play contributory roles in carcinogenesis and metastasis. Phenomenal strides have been made in leveraging our scientific knowledge altogether to a new level of maturity. Rapidly accumulating wealth of information has underlined a myriad of transduction cascades which can be pharmaceutically exploited for cancer prevention/inhibition. Natural products serve as a treasure trove and compel interdisciplinary researchers to study the cancer chemopreventive roles of wide-ranging natural products in cell culture and preclinical studies. Experimental research related to thymoquinone has gradually gained momentum because of the extra-ordinary cancer chemopreventive multifunctionalities of thymoquinone. In this mini-review, we provide an overview of different cell signaling cascades reported to be regulated by thymoquinone for cancer chemoprevention. Essentially, thymoquinone efficacy has also been notably studied in animal models, which advocates for a rationale-based transition of thymoquinone from the pre-clinical pipeline to clinical trials.
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Moon S, Zhung W, Yang S, Lim J, Kim WY. PIGNet: a physics-informed deep learning model toward generalized drug-target interaction predictions. Chem Sci 2022; 13:3661-3673. [PMID: 35432900 PMCID: PMC8966633 DOI: 10.1039/d1sc06946b] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/06/2022] [Indexed: 12/21/2022] Open
Abstract
Recently, deep neural network (DNN)-based drug-target interaction (DTI) models were highlighted for their high accuracy with affordable computational costs. Yet, the models' insufficient generalization remains a challenging problem in the practice of in silico drug discovery. We propose two key strategies to enhance generalization in the DTI model. The first is to predict the atom-atom pairwise interactions via physics-informed equations parameterized with neural networks and provides the total binding affinity of a protein-ligand complex as their sum. We further improved the model generalization by augmenting a broader range of binding poses and ligands to training data. We validated our model, PIGNet, in the comparative assessment of scoring functions (CASF) 2016, demonstrating the outperforming docking and screening powers than previous methods. Our physics-informing strategy also enables the interpretation of predicted affinities by visualizing the contribution of ligand substructures, providing insights for further ligand optimization.
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Affiliation(s)
- Seokhyun Moon
- Department of Chemistry, KAIST 291 Daehak-ro, Yuseong-gu Daejeon 34141 Republic of Korea
| | - Wonho Zhung
- Department of Chemistry, KAIST 291 Daehak-ro, Yuseong-gu Daejeon 34141 Republic of Korea
| | - Soojung Yang
- Department of Chemistry, KAIST 291 Daehak-ro, Yuseong-gu Daejeon 34141 Republic of Korea
| | - Jaechang Lim
- HITS Incorporation 124 Teheran-ro, Gangnam-gu Seoul 06234 Republic of Korea
| | - Woo Youn Kim
- Department of Chemistry, KAIST 291 Daehak-ro, Yuseong-gu Daejeon 34141 Republic of Korea
- HITS Incorporation 124 Teheran-ro, Gangnam-gu Seoul 06234 Republic of Korea
- KI for Artificial Intelligence, KAIST 291 Daehak-ro, Yuseong-gu Daejeon 34141 Republic of Korea
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Shankar A, Gopinath S, Kollur SP, Sushma P, Jain AS, Patil SS, Srinivasa C, Shivalingaiah, Shivamallu C. Structural Diversity and Role of Phytochemicals against P38-α Mitogen-activated Protein Kinase and Epidermal Growth Factor Receptor Kinase Domain: A Privileged Computational Approach. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2021; 15:2263-2269. [DOI: 10.22207/jpam.15.4.48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Computational databases and tools in recent times have been proved to provide an essential aid for anticancer studies in the field of oncology. Molecular docking studies facilitate the structural diversity of plant-derived phytomolecules having anticancer properties against receptor proteins involved in cancer signaling pathways. The current study involves the investigation of phytocompounds-agasthisflavone, anacardic acid, zoapatanolide A, a purified product of the plant extract Amarogopinois546 were subjected to docking studies on p38-α MAPK and EGFR Kinase domain. The effectiveness of this study was evaluated by comparing the docking interactions of a standard drug, doxorubicin against the receptor molecules. The docking study is analyzed by compound estimated with lowest binding energy is considered to have the highest affinity towards the active site of the receptor proteins. The isolated plant compound Amarogopinois546 displayed the least binding score with a large number of hydrogen bonds and hydrophobic interactions towards the P38α MAP kinase receptor in comparison with the EGFR kinase domain. This preliminary result can strongly be supported for carrying out experimental evaluation in near future.
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Elbadawy M, Sato Y, Mori T, Goto Y, Hayashi K, Yamanaka M, Azakami D, Uchide T, Fukushima R, Yoshida T, Shibutani M, Kobayashi M, Shinohara Y, Abugomaa A, Kaneda M, Yamawaki H, Usui T, Sasaki K. Anti-tumor effect of trametinib in bladder cancer organoid and the underlying mechanism. Cancer Biol Ther 2021; 22:357-371. [PMID: 34034619 PMCID: PMC8386751 DOI: 10.1080/15384047.2021.1919004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/21/2021] [Accepted: 04/15/2021] [Indexed: 02/06/2023] Open
Abstract
Bladder cancer (BC), a main neoplasm of urinary tract, is usually inoperable and unresponsive to chemotherapy. As a novel experimental model for muscle-invasive BC, we previously established a culture method of dog BC organoids. In the present study, the detailed in vitro and in vivo anti-tumor effects of trametinib were investigated by using this model. In each BC organoid strain, epidermal growth factor receptor (EGFR)/ERK signaling was upregulated compared with normal bladder cells. Trametinib even at a low concentration inhibited the cell viability of BC organoids and the activation of ERK through decreasing expression of c-Myc, ELK1, SIK1, and PLA2G4A. Trametinib arrested cell cycle of BC with few apoptosis. Dual treatment of BC organoids with trametinib and YAP inhibitor, verteporfin extremely inhibited the cell viability with apoptosis induction. Moreover, trametinib induced basal to luminal differentiation of BC organoids by upregulating luminal markers and downregulating basal ones. In vivo, trametinib decreased the tumor growth of BC organoids in mice and the xenograft-derived organoids from trametinib-administered mice showed enhanced sensitivity to carboplatin due to MSH2 upregulation. Our data suggested a new strategy of trametinib-YAP inhibitor or trametinib-carboplatin combination as a promising treatment of BC.
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Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt
| | - Yomogi Sato
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Takashi Mori
- Laboratory of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- Center for Highly Advanced Integration of Nano and Life Sciences, Gifu University (G-CHAIN), Gifu, Japan
| | - Yuta Goto
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Kimika Hayashi
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Megumi Yamanaka
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Daigo Azakami
- Department of Veterinary Clinical Oncology, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Tsuyoshi Uchide
- Department of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Ryuji Fukushima
- Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Mio Kobayashi
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Yuta Shinohara
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Pet Health & Food Division, Iskara Industry CO., LTD, Chuo-ku, Japan
| | - Amira Abugomaa
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Masahiro Kaneda
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
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12
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Rahimi K, Hassanzadeh K, Khanbabaei H, Haftcheshmeh SM, Ahmadi A, Izadpanah E, Mohammadi A, Sahebkar A. Curcumin: A Dietary Phytochemical for Targeting the Phenotype and Function of Dendritic Cells. Curr Med Chem 2021; 28:1549-1564. [PMID: 32410550 DOI: 10.2174/0929867327666200515101228] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 04/05/2020] [Accepted: 04/19/2020] [Indexed: 11/22/2022]
Abstract
Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context, DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hence, dysregulated DCs are the most attractive pharmacological target for the development of new therapies aiming at reducing their immunogenicity and at enhancing their tolerogenicity. Curcumin is the polyphenolic phytochemical component of the spice turmeric with a wide range of pharmacological activities. It acts in several ways as a modulator of DCs and converts them into tolerogenic DCs. Tolerogenic DCs possess anti-inflammatory and immunomodulatory activities that regulate the immune responses in health and disease. Curcumin by blocking maturation markers, cytokines and chemokines expression, and disrupting the antigen-presenting machinery of DCs render them non- or hypo-responsive to immunostimulants. It also reduces the expression of co-stimulatory and adhesion molecules on DCs and prevents them from both migration and antigen presentation but enhances their endocytosis capacity. Hence, curcumin causes DCs-inducing regulatory T cells and dampens CD4+ T helper 1 (Th1), Th2, and Th17 polarization. Inhibition of transcription factors such as NF-κB, AP-1, MAPKs (p38, JNK, ERK) and other intracellular signaling molecules such as JAK/STAT/SOCS provide a plausible explanation for most of these observations. In this review, we summarize the potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses.
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Affiliation(s)
- Kaveh Rahimi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Kambiz Hassanzadeh
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed M Haftcheshmeh
- Department of Medical Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91766-99199, Iran
| | - Abbas Ahmadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Esmael Izadpanah
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Asadollah Mohammadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
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13
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Wei J, Liu R, Hu X, Liang T, Zhou Z, Huang Z. MAPK signaling pathway-targeted marine compounds in cancer therapy. J Cancer Res Clin Oncol 2021; 147:3-22. [PMID: 33389079 DOI: 10.1007/s00432-020-03460-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/06/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE This paper reviews marine compounds that target the mitogen-activated protein kinase (MAPK) signaling pathway and their main sources, chemical structures, major targeted cancers and possible mechanisms to provide comprehensive and basic information for the development of marine compound-based antitumor drugs in clinical cancer therapy research. METHODS This paper searched the PubMed database using the keywords "cancer", "marine*" and "MAPK signaling pathway"; this search was supplemented by the literature-tracing method. The marine compounds screened for review in this paper are pure compounds with a chemical structure and have antitumor effects on more than one tumor cell line by targeting the MAPK signaling pathway. The PubChem database was used to search for the PubMed CID and draw the chemical structures of the marine compounds. RESULTS A total of 128 studies were searched, and 32 marine compounds with unique structures from extensive sources were collected for this review. These compounds are cytotoxic to cancer cell lines, although their targets are still unclear. This paper describes their anticancer effect mechanisms and the protein expression changes in the MAPK pathway induced by these marine compound treatments. This review is the first to highlight MAPK signaling pathway-targeted marine compounds and their use in cancer therapy. CONCLUSION The MAPK signaling pathway is a promising potential target for cancer therapy. Searching for marine compounds that exert anticancer effects by targeting the MAPK signaling pathway and developing them into new marine anticancer drugs will be beneficial for cancer treatment.
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Affiliation(s)
- Jiaen Wei
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, Guangdong, China
| | - Ruining Liu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, Guangdong, China
| | - Xiyun Hu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, Guangdong, China
| | - Tingen Liang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, Guangdong, China
| | - Zhiran Zhou
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, Guangdong, China
| | - Zunnan Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Dongguan, 523808, Guangdong, China. .,Marine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang, 524023, Guangdong, China.
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14
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Tsang YH, Wang Y, Kong K, Grzeskowiak C, Zagorodna O, Dogruluk T, Lu H, Villafane N, Bhavana VH, Moreno D, Elsea SH, Liang H, Mills GB, Scott KL. Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression. eLife 2020; 9:48963. [PMID: 32270762 PMCID: PMC7164953 DOI: 10.7554/elife.48963] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 04/06/2020] [Indexed: 12/19/2022] Open
Abstract
The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression.
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Affiliation(s)
- Yiu Huen Tsang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.,Cell, Develop & Cancer Biology, Oregon Health & Science University, Portland, United States
| | - Yumeng Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, United States
| | - Kathleen Kong
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Caitlin Grzeskowiak
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Oksana Zagorodna
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Turgut Dogruluk
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Hengyu Lu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Nicole Villafane
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.,Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, United States
| | | | - Daniela Moreno
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Sarah H Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Han Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, United States.,Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, United States
| | - Gordon B Mills
- Cell, Develop & Cancer Biology, Oregon Health & Science University, Portland, United States.,Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, United States
| | - Kenneth L Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
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15
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Xu W, Wang Z, Li K, Jin R. Huai Qi Huang Potentiates Dexamethasone-Mediated Lethality in Acute Lymphoblastic Leukemia Cells by Upregulating Glucocorticoid Receptor α. Med Sci Monit 2020; 26:e921649. [PMID: 32065117 PMCID: PMC7043341 DOI: 10.12659/msm.921649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background Glucocorticoids are important components of a number of chemotherapeutic regimens used to treat pediatric acute lymphoblastic leukemia (ALL). A primary cause of treatment failure of ALL is acquired resistance to glucocorticoids. Recently, traditional Chinese medicines were effectively used to treat solid tumors. Thus, the aim of this study was to investigate whether Huai Qi Huang (HQH), a traditional Chinese medicine, increased the efficacy of glucocorticoids in the treatment of ALL, and if so, to determine the underlying mechanism. Material/Methods Various concentrations of HQH were used to treat Jurkat and Nalm-6 cells for 24 to 72 hours. Subsequently, cells were co-treated with HQH and the glucocorticoid receptor agonist, dexamethasone (DEX), or a MEK inhibitor (PD98059) to verify the synergistic effects on apoptosis in Jurkat and Nalm-6 cells for 24 hours. Cell Counting Kit-8 assay and flow cytometry were used to measure cell viability and apoptosis, respectively. Protein and mRNA expression levels were assessed using western blotting and quantitative polymerase chain reaction. Results The results revealed that cell survival was reduced and apoptosis was increased as the HQH concentration was increased, and this was accompanied with increases in the levels of BAX, cleaved-caspase-3 and glucocorticoid receptor α (GRα) and decreases in the levels of Bcl-2 and phospho-ERK (pERK). Glucocorticoid receptor β (GRβ) and total ERK (t-ERK) had no significant changes. Combined treatment with HQH and DEX or PD98059 increased apoptosis in Jurkat and Nalm-6 cells, and concurrently increased BAX, cleaved-caspase-3, GILZ, NFKBIA, and GRα and decreased Bcl-2 and pERK. Conclusions HQH enhanced the sensitivity of ALL cells to glucocorticoids by increasing the expression of GRα and inhibiting the MEK/ERK pathway, thus providing a rational foundation for the treatment of ALL with HQH.
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Affiliation(s)
- Wenfu Xu
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Zhujun Wang
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Kun Li
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Runming Jin
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
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Sinulariolide Inhibits Gastric Cancer Cell Migration and Invasion through Downregulation of the EMT Process and Suppression of FAK/PI3K/AKT/mTOR and MAPKs Signaling Pathways. Mar Drugs 2019; 17:md17120668. [PMID: 31783709 PMCID: PMC6950622 DOI: 10.3390/md17120668] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/21/2019] [Accepted: 11/26/2019] [Indexed: 12/19/2022] Open
Abstract
Cancer metastasis is the main cause of death in cancer patients; however, there is currently no effective method to predict and prevent metastasis of gastric cancer. Therefore, gaining an understanding of the molecular mechanism of tumor metastasis is important for the development of new drugs and improving the survival rate of patients who suffer from gastric cancer. Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. We employed sinulariolide and gastric cancer cells in experiments such as MTT, cell migration assays, cell invasion assays, and Western blotting analysis. Analysis of cell migration and invasion capabilities showed that the inhibition effects on cell metastasis and invasion increased with sinulariolide concentration in AGS and NCI-N87 cells. Immunostaining analysis showed that sinulariolide significantly reduced the protein expressions of MMP-2, MMP-9, and uPA, but the expressions of TIMP-1 and TIMP-2 were increased, while FAK, phosphorylated PI3K, phosphorylated AKT, phosphorylated mTOR, phosphorylated JNK, phosphorylated p38MAPK, and phosphorylated ERK decreased in expression with increasing sinulariolide concentration. From the results, we inferred that sinulariolide treatment in AGS and NCI-N87 cells reduced the activities of MMP-2 and MMP-9 via the FAK/PI3K/AKT/mTOR and MAPKs signaling pathways, further inhibiting the invasion and migration of these cells. Moreover, sinulariolide altered the protein expressions of E-cadherin and N-cadherin in the cytosol and Snail in the nuclei of AGS and NCI-N87 cells, which indicated that sinulariolide can avert the EMT process. These findings suggested that sinulariolide is a potential chemotherapeutic agent for development as a new drug for the treatment of gastric cancer.
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17
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Kushwaha P, Ahmad N, Dhar YV, Verma A, Haldar S, Mulani FA, Trivedi PK, Mishra PR, Thulasiram HV, Trivedi R. Estrogen receptor activation in response to Azadirachtin A stimulates osteoblast differentiation and bone formation in mice. J Cell Physiol 2019; 234:23719-23735. [DOI: 10.1002/jcp.28940] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 05/15/2019] [Accepted: 05/22/2019] [Indexed: 12/23/2022]
Affiliation(s)
| | - Naseer Ahmad
- Endocrinology CSIR‐Central Drug Research Institute Lucknow India
| | - Yogeshwar V. Dhar
- Molecular Biology and Biotechnology CSIR‐National Botanical Research Institute Lucknow India
| | - Ashwni Verma
- Pharmaceutics Division CSIR‐Central Drug Research Institute Lucknow India
| | - Saikat Haldar
- Organic Chemistry Division CSIR‐National Chemical Laboratory Pune India
| | - Fayaj A. Mulani
- Organic Chemistry Division CSIR‐National Chemical Laboratory Pune India
| | - Prabodh K. Trivedi
- Molecular Biology and Biotechnology CSIR‐National Botanical Research Institute Lucknow India
| | - Prabhat R. Mishra
- Pharmaceutics Division CSIR‐Central Drug Research Institute Lucknow India
| | | | - Ritu Trivedi
- Endocrinology CSIR‐Central Drug Research Institute Lucknow India
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18
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Khan MF, Verma G, Alam P, Akhter M, Bakht MA, Hasan SM, Shaquiquzzaman M, Alam MM. Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies. Comput Biol Med 2019; 110:175-185. [PMID: 31173941 DOI: 10.1016/j.compbiomed.2019.05.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 05/30/2019] [Accepted: 05/30/2019] [Indexed: 01/24/2023]
Abstract
In the present study, a series of dibenzepinones, dibenzoxepines, and benzosuberones targeting p38α MAP kinase were subjected to pharmacophore modelling, 3D-QSAR and molecular docking studies. The IC50 values for these 67 compounds ranged between 0.003 and 6.80 μM. A five-point model (DDHHR.8) was generated using these compounds. This model was found to be statistically significant and was found to have high correlation (R2 = 0.98), cross-validation coefficient (Q2 = 0.95) and F (330) values at six component PLS factor. Tests were performed to ascertain the efficacy of the generated model. These tests included external validation, Tropsha's test for predictive ability, Y-randomisation test and domain of applicability (APD). In order to check the restrictivity of the model, enrichment studies were performed with inactive compounds by using decoy set molecules. To evaluate the effectiveness of the docking protocol, the co-crystallised ligand was extracted from the ligand-binding domain of the protein and was re-docked into the same position. Both the conformers were then superimposed, suggesting satisfactory docking parameters with an RMSD value of less than 1.0 Å (0.853 Å). A 10 ns molecular dynamics simulation confirmed the docking results of the 3UVP-ligand complex and the presumed active conformation. The outcome of the present study provides insight into the molecular features that promote bioactivity and can be exploited for the prediction of novel potent p38α MAP kinase inhibitors before carrying out their synthesis and anticancer evaluation.
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Affiliation(s)
- Mohemmed Faraz Khan
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Garima Verma
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Perwez Alam
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mymoona Akhter
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Md Afroz Bakht
- Department of Chemistry, College of Science and Humanities, Prince Sattam Bin Abdulaziz University, P.O. Box- 173, Al-Kharj, Saudi Arabia
| | - Syed Misbahul Hasan
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Integral University, Lucknow, 226026, India
| | - Mohammad Shaquiquzzaman
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Mohammad Mumtaz Alam
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
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Fourie C, Davis T, Kriel J, Engelbrecht AM. The paracrine effects of fibroblasts on Doxorubicin-treated breast cancer cells. Exp Cell Res 2019; 381:280-287. [PMID: 31121155 DOI: 10.1016/j.yexcr.2019.05.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/14/2019] [Accepted: 05/16/2019] [Indexed: 12/20/2022]
Abstract
Breast cancer is frequently diagnosed in women and poses a major health problem throughout the world. Currently, the unresponsiveness of cancer cells to chemotherapeutics is a major concern. During chemotherapeutic treatment with Doxorubicin, neighbouring cells in the tumor microenvironment are also damaged. Depending on the concentration of Doxorubicin, apoptotic or senescent fibroblasts in the tumor microenvironment can then secrete a variety of bioactive molecules which promote tumor growth, metastasis and drug resistance. Mouse embryonic fibroblasts (MEFs) were treated with Doxorubicin to induce apoptosis and senescence respectively. Conditioned media was collected from the MEFs and was used to assess the paracrine effects between fibroblasts and E0771 murine breast cancer cells. Senescent fibroblasts significantly increased cell viability in E0771 cells following Doxorubicin treatment by activating Akt and ERK. Autophagy contributed to cancer cell death and not to treatment resistance in breast cancer cells. Our results highlight the complexity of the tumor microenvironment where chemotherapeutic agents such as Doxorubicin can induce significant changes fibroblasts which can affect tumor growth via the secretion of paracrine factors. Here we have demonstrated that those secreted paracrine factors enhance breast cancer growth and induce therapeutic resistance through the evasion of apoptotic cell death.
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Affiliation(s)
- Carla Fourie
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
| | - Tanja Davis
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
| | - Jurgen Kriel
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
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20
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RSK2-Mediated ELK3 Activation Enhances Cell Transformation and Breast Cancer Cell Growth by Regulation of c-fos Promoter Activity. Int J Mol Sci 2019; 20:ijms20081994. [PMID: 31018569 PMCID: PMC6515335 DOI: 10.3390/ijms20081994] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 04/17/2019] [Accepted: 04/19/2019] [Indexed: 12/14/2022] Open
Abstract
Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.
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Abdelhafez OM, Ahmed EY, Abdel Latif NA, Arafa RK, Abd Elmageed ZY, Ali HI. Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer, synthesized from oxygen heterocyclic natural compounds. Bioorg Med Chem 2019; 27:1308-1319. [DOI: 10.1016/j.bmc.2019.02.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/30/2019] [Accepted: 02/14/2019] [Indexed: 01/06/2023]
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Feng J, Jin Y, Peng J, Wei L, Cai Q, Yan Z, Lai Z, Lin J. Hedyotis diffusa willd extract suppresses colorectal cancer growth through multiple cellular pathways. Oncol Lett 2017; 14:8197-8205. [PMID: 29344262 PMCID: PMC5755052 DOI: 10.3892/ol.2017.7244] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 07/21/2017] [Indexed: 12/15/2022] Open
Abstract
The development of colorectal cancer (CRC) is strongly associated with the imbalance of various intracellular signal transduction cascades, including protein kinase B (AKT), mitogen-activated protein kinase 1 (MAPK), signal transducer and activator of transcription 3 (STAT3), as well as crosstalk between these signaling networks. At present, anti-tumor agents are often single-targeted and therefore are not always therapeutically effective. Moreover, long-term use of these anti-tumor agents often generates drug resistance and potential side effects. These problems highlight the urgent need for the development of novel and more effective anti-cancer drugs. Hedyotis diffusa Willd (HDW) has been used as a major component in traditional Chinese medicine for the clinical treatment of colorectal cancer, with a limited number of adverse effects. However, the molecular mechanisms, which underlie its anti-cancer activity, still require further elucidation. In the present study, using xenograft models and various different human CRC cell lines, the efficacy of the ethanol extract of HDW (EEHDW) against tumor growth was evaluated, and its underlying molecular mechanisms of action were investigated. It was demonstrated that EEHDW was able to inhibit cancer growth in vivo and in vitro. Furthermore, EEHDW was able to suppress the activation of several CRC-associated signaling pathways and was able to regulate the expression of various inflammatory and angiogenic factors. This resulted in the induction of apoptosis and inhibition of cellular proliferation, as well as tumor angiogenesis. The present study demonstrated that EEHDW is able to exhibit anti-cancer activity due to its ability to affect multiple intracellular targets, which suggests that it may be a novel multi-potent therapeutic agent for the treatment of colorectal cancer.
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Affiliation(s)
- Jianyu Feng
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Yiyi Jin
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Jun Peng
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Lihui Wei
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Qiaoyan Cai
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Zhaokun Yan
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Zijun Lai
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Jiumao Lin
- Biomedical Research Center of Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
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Cervello M, Augello G, Cusimano A, Emma MR, Balasus D, Azzolina A, McCubrey JA, Montalto G. Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma. Adv Biol Regul 2017; 65:59-76. [PMID: 28619606 DOI: 10.1016/j.jbior.2017.06.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/24/2017] [Accepted: 06/04/2017] [Indexed: 06/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and represents the second most frequently cancer and third most common cause of death from cancer worldwide. At advanced stage, HCC is a highly aggressive tumor with a poor prognosis and with very limited response to common therapies. Therefore, there is still the need for new effective and well-tolerated therapeutic strategies. Molecular-targeted therapies hold promise for HCC treatment. One promising molecular target is the multifunctional serine/threonine kinase glycogen synthase kinase 3 (GSK-3). The roles of GSK-3β in HCC remain controversial, several studies suggested a possible role of GSK-3β as a tumor suppressor gene in HCC, whereas, other studies indicate that GSK-3β is a potential therapeutic target for this neoplasia. In this review, we will focus on the different roles that GSK-3 plays in HCC and its interaction with signaling pathways implicated in the pathogenesis of HCC, such as Insulin-like Growth Factor (IGF), Notch, Wnt/β-catenin, Hedgehog (HH), and TGF-β pathways. In addition, the pivotal roles of GSK3 in epithelial-mesenchymal transition (EMT), invasion and metastasis will be also discussed.
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Affiliation(s)
- Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
| | - Giuseppa Augello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Maria Rita Emma
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Daniele Balasus
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Antonina Azzolina
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Giuseppe Montalto
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy; Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy
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Park JR, Lee MC, Moon SC, Kim J, Ha KT, Park EJ, Hong C, Seo BD, Kim BJ. Scutellaria baicalensis Georgi induces caspase-dependent apoptosis via mitogen activated protein kinase activation and the generation of reactive oxygen species signaling pathways in MCF-7 breast cancer cells. Mol Med Rep 2017; 16:2302-2308. [PMID: 28627691 DOI: 10.3892/mmr.2017.6798] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 04/28/2017] [Indexed: 11/06/2022] Open
Abstract
Scutellaria baicalensis Georgi extract (SBGE) is used in traditional herbal medicine and has also been used clinically to ameliorate the symptoms of various inflammatory diseases and cancer. In women, breast cancer is one of the most common diseases and numerous women succumb to it. The present study was undertaken to investigate the mechanism responsible for the SBGE‑induced apoptosis of MCF‑7 human breast cancer cells. SBGE was administered to cells at concentrations between 100 and 500 mg/ml, and cell viabilities were identified using an MTT assay. B‑cell lymphoma 2 (Bcl-2) and Bcl-2 X‑associated protein (Bax) family members were identified by western blotting, and the mRNA expression levels of the pro‑apoptosis genes Fas, Fas ligand (FasL) and tumor necrosis factor (TNF)‑α were assessed by reverse transcription‑polymerase chain reaction. It was identified that SBGE treatment for 24 h inhibited MCF‑7 proliferation and increased the sub‑G1 phase ratio. SBGE suppressed mitochondrial membrane potentials and SBGE‑induced apoptotic cell death was identified to be associated with downregulation of Bcl‑2, but upregulation of Bax. SBGE‑activated caspases 3 and 9, and increased reactive oxygen species generation. However, SBGE had no effect on the expression levels of Fas, FasL or TNF‑α. Furthermore, mitogen‑activated protein kinase and C‑Jun N‑terminal kinase inhibitors inhibited SBGE‑induced cell death. These results suggested that SBGE be considered as an agent for the treatment of breast cancer.
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Affiliation(s)
- Jin Ryeong Park
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Min Cheol Lee
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Seong-Cheol Moon
- Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Junghoon Kim
- Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Ki-Tae Ha
- Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
| | - Eun Jung Park
- Department of Physiology, Seoul National University College of Medicine, Seoul 110‑799, Republic of Korea
| | - Chansik Hong
- Department of Physiology, Chosun University College of Medicine, Gwangju 61452, Republic of Korea
| | - Byoung-Do Seo
- Department of Physical Therapy, Kyungwoon University College of Health, Gumi 730‑739, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 50612, Republic of Korea
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25
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Expression of adenylate kinase fused MEK1R4F in Escherichia coli and its application in ERK phosphorylation. Biotechnol Lett 2017; 39:1553-1558. [PMID: 28748350 DOI: 10.1007/s10529-017-2385-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 06/22/2017] [Indexed: 01/29/2023]
Abstract
OBJECTIVE To construct a highly expressed and active MEK1R4F (a constitutively active form of mitogen-activated protein kinase kinase 1) by fusion of soluble adenylate kinase (Adk) tag, resulting in Adk-MEK1R4F protein suitable for preparation of phosphorylated ERK. RESULTS We fused the Adk to the N-terminus of MEK1R4F through overlapping PCR. The expression of Adk-MEK1R4F fusion protein increased ~10-fold in Escherichia coli, and was purified to 95% via two purification steps including Ni-NTA and Q Sepharose fast flow (QFF) chromatography. The purified Adk-MEK1R4F protein was functional for ERK phosphorylation and could use ADP in addition to ATP. The Adk-MEK1R4F had higher catalytic activity than regular MEK1R4F both in vitro and in cell-free extracts system. CONCLUSIONS Adenylate kinase was used as a soluble tag to facilitate MEK1R4F protein expression and its application in large-scale phosphorylated ERK1/2 preparation and purification.
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26
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Chadha R, Bhalla Y, Jain A, Chadha K, Karan M. Dietary Soy Isoflavone: A Mechanistic Insight. Nat Prod Commun 2017. [DOI: 10.1177/1934578x1701200439] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Soy, a major component of the diet for centuries contains the largest concentration of isoflavones, a class of phytoestrogens. A variety of health benefits are associated with the consumption of soy primarily because of the isoflavones genistein, daidzein, and glycitein with a potential protective effect against a number of chronic diseases. Owing to the pharmaceutical and nutraceutical properties allied with isoflavonoids and their use in functional foods, there is a growing interest in these compounds. This review throws light on the chemistry, and significant pharmacological and biopharmaceutical aspects of soy isoflavones. This article critically describes the mechanisms of action, infers conclusions and shows opportunity for future research.
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Affiliation(s)
- Renu Chadha
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Yashika Bhalla
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Ankita Jain
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Kunal Chadha
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Maninder Karan
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
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Amin KM, Syam YM, Anwar MM, Ali HI, Abdel-Ghani TM, Serry AM. Synthesis and molecular docking studies of new furochromone derivatives as p38α MAPK inhibitors targeting human breast cancer MCF-7 cells. Bioorg Med Chem 2017; 25:2423-2436. [PMID: 28291685 DOI: 10.1016/j.bmc.2017.02.065] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 02/27/2017] [Indexed: 12/12/2022]
Abstract
Based on the reported high expression of p38α MAP kinase in invasive breast cancers and the activity of different functionalized chromone derivatives as p38α inhibitors, a new set of 4,9-dimethoxy/4-methoxy-7-methyl-5-oxo-5H-furo[3,2-g]chromone derivatives were efficiently synthesized aiming to introduce new p38α MAP kinase suppressors as new anti-breast cancer tools. Using GOLD program, molecular docking study of the target compounds into p38α MAP kinase binding pocket was performed to highlight their scores, mode of binding and the important interactions to the amino acid residues of the enzyme. MTT assay investigated that fifteen target compounds produced marked cytotoxic potency higher than that obtained by Doxorubicin against MCF-7 cancer cells of IC50 values ranging from 0.007 to 0.17μM vs IC50; 0.62μM of doxorubicin. Eleven selected compounds were evaluated for their inhibitory potency against p38α MAPK kinase. The derivatives IVa, Va,b, VIa, IXb and XIIIa represented significant activity (IC50; 0.19-0.67μM) comparing to the reference drug SB203580 (IC50; 0.50μM). In virtue of its promising cytotoxic and p38α MAP kinase inhibition potency, the furochromone derivative IXb was selected as a representative example to investigate its mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cell lines. The results showed that the compound IXb induced cell cycle cessation at G2/M phase preventing its mitotic cycle, alongside its noteworthy activation of caspases-9 and -3 which might mediate the apoptosis of MCF-7 cells.
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Affiliation(s)
- Kamelia M Amin
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt
| | - Yasmin M Syam
- Department of Therapeutical Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt.
| | - Manal M Anwar
- Department of Therapeutical Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt
| | - Hamed I Ali
- Pharmaceutical Sciences Dept., Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, TX, USA
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Propylene Glycol Alginate Sodium Sulfate Alleviates Cerulein-Induced Acute Pancreatitis by Modulating the MEK/ERK Pathway in Mice. Mar Drugs 2017; 15:md15020045. [PMID: 28218693 PMCID: PMC5334625 DOI: 10.3390/md15020045] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 01/17/2017] [Indexed: 12/13/2022] Open
Abstract
Previous studies have focused on the effects of propylene glycol alginate sodium sulfate (PSS) against thrombosis, but the anti-inflammatory potential is unknown. Therefore, we specifically focused on the protective effects of PSS on cerulein-induced acute pancreatitis (AP) using a mouse model, and investigated the mechanism of PSS on autophagy and apoptosis via the Mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Cerulein (100 ug/kg) was used to induce AP by ten intraperitoneal injections at hourly intervals in Balb/C mice. Pretreatment with vehicle or PSS was carried out 1 h before the first cerulein injection and two doses (25 mg/kg and 50 mg/kg) of PSS were injected intraperitoneally. The severity of AP was assessed by pathological score, biochemistry, pro-inflammatory cytokine levels, myeloperoxidase (MPO) activity and MEK/ERK activity. Furthermore, pancreatic histological scores, serum amylase and lipase activities, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β interleukin (IL)-6 levels, and MPO activity were significantly reduced by PSS via up-regulated MEK/ERK activity. The representative molecules of apoptosis and autophagy, such as Bcl-2, Bax, Lc-3, Beclin-1, P62, were remarkably reduced. Taken together, these results indicate that PSS attenuates pancreas injury by inhibiting autophagy and apoptosis through a mechanism involving the MEK/ERK signaling pathway.
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29
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Akizuki R, Shimobaba S, Matsunaga T, Endo S, Ikari A. Claudin-5, -7, and -18 suppress proliferation mediated by inhibition of phosphorylation of Akt in human lung squamous cell carcinoma. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1864:293-302. [PMID: 27884700 DOI: 10.1016/j.bbamcr.2016.11.018] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/26/2016] [Accepted: 11/18/2016] [Indexed: 12/11/2022]
Abstract
Abnormal expression of claudin (CLDN) subtypes has been reported in various solid cancers. However, it is unknown which subtype plays a key role in the regulation of proliferation in cancer cells. The expression of CLDN3-5, 7, and 18 in human lung squamous carcinoma tissues was lower than that in normal tissue. Here, we examined which combination of exogenous CLDNs expression inhibits proliferation and the molecular mechanism using human lung squamous RERF-LC-AI cells. Real-time polymerase chain reaction and western blotting showed that CLDN3-5, 7, and 18 are little expressed in RERF-LC-AI cells. In the exogenously transfected cells, CLDN5, 7, and 18 were distributed in the cell-cell contact areas concomitant with ZO-1, a tight junctional scaffolding protein, whereas CLDN3 and 4 were not. Cell proliferation was individually and additively suppressed by CLDN5, 7, and 18. The expression of these CLDNs showed no cytotoxicity compared with mock cells. CLDN5, 7, and 18 increased p21 and decreased cyclin D1, resulting in the suppression of cell cycle G1-S transition. The expression of these CLDNs inhibited phosphorylation of Akt without affecting phosphorylated ERK1/2. Furthermore, these CLDNs inhibited the nuclear localization of Akt and its association with 3-phosphoinositide-dependent protein kinase-1 (PDK1). The suppression of G1-S transition caused by CLDN5, 7, and 18 was rescued by the expression of constitutively active-Akt. We suggest that the reduction of CLDN5, 7, and 18 expression loses the suppressive ability of interaction between PDK1 and Akt and causes sustained phosphorylation of Akt, resulting in the disordered proliferation in lung squamous carcinoma cells.
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Affiliation(s)
- Risa Akizuki
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Shun Shimobaba
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Toshiyuki Matsunaga
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Satoshi Endo
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University
| | - Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University.
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30
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Wu L, Sun J, Su X, Yu Q, Yu Q, Zhang P. A review about the development of fucoidan in antitumor activity: Progress and challenges. Carbohydr Polym 2016; 154:96-111. [PMID: 27577901 DOI: 10.1016/j.carbpol.2016.08.005] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/30/2016] [Accepted: 08/02/2016] [Indexed: 12/28/2022]
Abstract
Fucoidan is composed of l-fucose, sulfate groups and one or more small proportions of d-xylose, d-mannose, d-galactose, l-rhamnose, arabinose, glucose, d-glucuronic acid and acetyl groups in different kinds of brown seaweeds. Many reports have demonstrated that fucoidan has antitumor activities on various cancers. However, until now, few reviews have discussed the antitumor activity of fucoidan and few reports have summarized detailed molecular mechanisms of its actions and antitumor challenges of fucoidan specially. In this review, the antitumor signaling pathway mechanisms related to fucoidan are elucidated as much detail as possible. Besides, the factors affecting the anticancer effects of fucoidan, the structural characteristics of fucoidan with anticancer activities and the challenges for the further development of fucoidan are also summarized and evaluated. The existing similar and different conclusions are summarized in an attempt to provide guidelines to help further research, and finally contribute to go into market as chemotherapeumtics.
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Affiliation(s)
- Lei Wu
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
| | - Jing Sun
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
| | - Xitong Su
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
| | - Qiuli Yu
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
| | - Qiuyang Yu
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
| | - Peng Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
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31
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Chaves AFA, Navarro MV, Castilho DG, Calado JCP, Conceição PM, Batista WL. A conserved dimorphism-regulating histidine kinase controls the dimorphic switching in Paracoccidioides brasiliensis. FEMS Yeast Res 2016; 16:fow047. [PMID: 27268997 DOI: 10.1093/femsyr/fow047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2016] [Indexed: 02/05/2023] Open
Abstract
Paracoccidioides brasiliensis and P. lutzii, thermally dimorphic fungi, are the causative agents of paracoccidioidomycosis (PCM). Paracoccidioides infection occurs when conidia or mycelium fragments are inhaled by the host, which causes the Paracoccidioides cells to transition to the yeast form. The development of disease requires conidia inside the host alveoli to differentiate into yeast cells in a temperature-dependent manner. We describe the presence of a two-component signal transduction system in P. brasiliensis, which we investigated by expression analysis of a hypothetical protein gene (PADG_07579) that showed high similarity with the dimorphism-regulating histidine kinase (DRK1) gene of Blastomyces dermatitidis and Histoplasma capsulatum This gene was sensitive to environmental redox changes, which was demonstrated by a dose-dependent decrease in transcript levels after peroxide stimulation and a subtler decrease in transcript levels after NO stimulation. Furthermore, the higher PbDRK1 levels after treatment with increasing NaCl concentrations suggest that this histidine kinase can play a role as osmosensing. In the mycelium-yeast (M→Y) transition, PbDRK1 mRNA expression increased 14-fold after 24 h incubation at 37°C, consistent with similar observations in other virulent fungi. These results demonstrate that the PbDRK1 gene is differentially expressed during the dimorphic M→Y transition. Finally, when P. brasiliensis mycelium cells were exposed to a histidine kinase inhibitor and incubated at 37°C, there was a delay in the dimorphic M→Y transition, suggesting that histidine kinases could be targets of interest for PCM therapy.
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Affiliation(s)
- Alison F A Chaves
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Unidade José Alencar, Street São Nicolau, nº210, 4º floor, São Paulo 04023-900, Brazil
| | - Marina V Navarro
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Unidade José Alencar, Street São Nicolau, nº210, 4º floor, São Paulo 04023-900, Brazil
| | - Daniele G Castilho
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Unidade José Alencar, Street São Nicolau, nº210, 4º floor, São Paulo 04023-900, Brazil
| | - Juliana C P Calado
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Unidade José Alencar, Street São Nicolau, nº210, 4º floor, São Paulo 04023-900, Brazil
| | - Palloma M Conceição
- Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema 09913-030, São Paulo, Brazil
| | - Wagner L Batista
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Unidade José Alencar, Street São Nicolau, nº210, 4º floor, São Paulo 04023-900, Brazil Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema 09913-030, São Paulo, Brazil
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Kritsanawong S, Innajak S, Imoto M, Watanapokasin R. Antiproliferative and apoptosis induction of α-mangostin in T47D breast cancer cells. Int J Oncol 2016; 48:2155-65. [PMID: 26892433 DOI: 10.3892/ijo.2016.3399] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 02/08/2016] [Indexed: 11/06/2022] Open
Abstract
α-Mangostin extracted from mangosteen, Garcinia mangostana Linn. is known as 'queen of fruits'. The anticancer activity of α-mangostin through apoptosis induction and related signaling pathways in human breast cancer T47D cells was investigated. Human epidermal growth factor receptor 2 (HER2) and mitogen-activated protein kinase (MAPK) signaling have been shown to play important roles in apoptosis. The results showed that α-mangostin induced cell proliferation inhibition, DNA fragmentation, nuclear condensation, increased cleaved caspase-3 and cleaved caspase-9, but decreased Bcl-2 and Mcl-1 expression. Mitochondrial dysfunction and cytochrome c release were also detected. In addition, phosphorylation of ERα, HER2, PI3K, Akt and ERK1/2 were downregulated whereas p-JNK1/2 and p-p38 were upregulated. These results indicated that α-mangostin induced apoptosis associated with HER2/PI3K/Akt and MAPK signaling pathways suggesting that α-mangostin may be used as food supplement or a potential therapeutic compound for breast cancer.
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Affiliation(s)
- Somchai Kritsanawong
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Sukanda Innajak
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Masaya Imoto
- Department of Bioscience and Information, Faculty of Science and Technology, Keio University, Yokohama, Japan
| | - Ramida Watanapokasin
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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The role of natural polyphenols in cell signaling and cytoprotection against cancer development. J Nutr Biochem 2015; 32:1-19. [PMID: 27142731 DOI: 10.1016/j.jnutbio.2015.11.006] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/13/2015] [Accepted: 11/09/2015] [Indexed: 12/20/2022]
Abstract
The cytoprotective and anticancer action of dietary in-taken natural polyphenols has for long been attributed only to their direct radical scavenging activities. Currently it is well supported that those compounds display a broad spectrum of biological and pharmacological outcomes mediated by their complex metabolism, interaction with gut microbiota as well as direct interactions of their metabolites with key cellular signaling proteins. The beneficial effects of natural polyphenols and their synthetic derivatives are extensively studied in context of cancer prophylaxis and therapy. Herein we focus on cell signaling to explain the beneficial role of polyphenols at the three stages of cancer development: we review the recent proceedings about the impact of polyphenols on the cytoprotective antioxidant response and their proapoptotic action at the premalignant stage, and finally we present data showing how phenolic acids (e.g., caffeic, chlorogenic acids) and flavonols (e.g., quercetin) hamper the development of metastatic cancer.
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34
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The Chromone Alkaloid, Rohitukine, Affords Anti-Cancer Activity via Modulating Apoptosis Pathways in A549 Cell Line and Yeast Mitogen Activated Protein Kinase (MAPK) Pathway. PLoS One 2015; 10:e0137991. [PMID: 26405812 PMCID: PMC4583253 DOI: 10.1371/journal.pone.0137991] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 08/24/2015] [Indexed: 01/04/2023] Open
Abstract
The field of cancer research and treatment has made significant progress, yet we are far from having completely safe, efficient and specific therapies that target cancer cells and spare the healthy tissues. Natural compounds may reduce the problems related to cancer treatment. Currently, many plant products are being used to treat cancer. In this study, Rohitukine, a natural occurring chromone alkaloid extracted from Dysoxylum binectariferum, was investigated for cytotoxic properties against budding yeast as well as against lung cancer (A549) cells. We endeavored to specifically study Rohitukine in S. cerevisiae in the context of MAPK pathways as yeast probably represents the experimental model where the organization and regulation of MAPK pathways are best understood. MAPK are evolutionarily conserved protein kinases that transfer extracellular signals to the machinery controlling essential cellular processes like growth, migration, differentiation, cell division and apoptosis. We aimed at carrying out hypothesis driven studies towards targeting the important network of cellular communication, a critical process that gets awry in cancer. Employing mutant strains of genetic model system Saccharomyces cerevisiae. S. cerevisiae encodes five MAPKs involved in control of distinct cellular responses such as growth, differentiation, migration and apoptosis. Our study involves gene knockouts of Slt2 and Hog1 which are functional homologs of human ERK5 and mammalian p38 MAPK, respectively. We performed cytotoxicity assay to evaluate the effect of Rohitukine on cell viability and also determined the effects of drug on generation of reactive oxygen species, induction of apoptosis and expression of Slt2 and Hog1 gene at mRNA level in the presence of drug. The results of this study show a differential effect in the activity of drug between the WT, Slt2 and Hog1 gene deletion strain indicating involvement of MAPK pathway. Further, we investigated Rohitukine induced cytotoxic effects in lung cancer cells and stimulated the productions of ROS after exposure for 24 hrs. Results from western blotting suggest that Rohitukine triggered apoptosis in A549 cell line through upregulation of p53, caspase9 and down regulation of Bcl-2 protein. The scope of this study is to understand the mechanism of anticancer activity of Rohitukine to increase the repertoire of anticancer drugs, so that problem created by emergence of resistance towards standard anticancer compounds can be alleviated.
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Singh BN, Singh HB, Singh A, Naqvi AH, Singh BR. Dietary phytochemicals alter epigenetic events and signaling pathways for inhibition of metastasis cascade: phytoblockers of metastasis cascade. Cancer Metastasis Rev 2015; 33:41-85. [PMID: 24390421 DOI: 10.1007/s10555-013-9457-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cancer metastasis is a multistep process in which a cancer cell spreads from the site of the primary lesion, passes through the circulatory system, and establishes a secondary tumor at a new nonadjacent organ or part. Inhibition of cancer progression by dietary phytochemicals (DPs) offers significant promise for reducing the incidence and mortality of cancer. Consumption of DPs in the diet has been linked to a decrease in the rate of metastatic cancer in a number of preclinical animal models and human epidemiological studies. DPs have been reported to modulate the numerous biological events including epigenetic events (noncoding micro-RNAs, histone modification, and DNA methylation) and multiple signaling transduction pathways (Wnt/β-catenin, Notch, Sonic hedgehog, COX-2, EGFR, MAPK-ERK, JAK-STAT, Akt/PI3K/mTOR, NF-κB, AP-1, etc.), which can play a key role in regulation of metastasis cascade. Extensive studies have also been performed to determine the molecular mechanisms underlying antimetastatic activity of DPs, with results indicating that these DPs have significant inhibitory activity at nearly every step of the metastatic cascade. DPs have anticancer effects by inducing apoptosis and by inhibiting cell growth, migration, invasion, and angiogenesis. Growing evidence has also shown that these natural agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways. In this review, we discuss the variety of molecular mechanisms by which DPs regulate metastatic cascade and highlight the potentials of these DPs as promising therapeutic inhibitors of cancer.
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Affiliation(s)
- B N Singh
- Research and Development Division, Sowbhagya Biotech Private Limited, Cherlapally, Hyderabad, 500051, Andhra Pradesh, India
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Begum S, Achary PGR. Simplified molecular input line entry system-based: QSAR modelling for MAP kinase-interacting protein kinase (MNK1). SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2015; 26:343-361. [PMID: 25967103 DOI: 10.1080/1062936x.2015.1039577] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Quantitative structure-activity relationship (QSAR) models were built for the prediction of inhibition (pIC50, i.e. negative logarithm of the 50% effective concentration) of MAP kinase-interacting protein kinase (MNK1) by 43 potent inhibitors. The pIC50 values were modelled with five random splits, with the representations of the molecular structures by simplified molecular input line entry system (SMILES). QSAR model building was performed by the Monte Carlo optimisation using three methods: classic scheme; balance of correlations; and balance correlation with ideal slopes. The robustness of these models were checked by parameters as rm(2), r(*)m(2), [Formula: see text] and randomisation technique. The best QSAR model based on single optimal descriptors was applied to study in vitro structure-activity relationships of 6-(4-(2-(piperidin-1-yl) ethoxy) phenyl)-3-(pyridin-4-yl) pyrazolo [1,5-a] pyrimidine derivatives as a screening tool for the development of novel potent MNK1 inhibitors. The effects of alkyl group, -OH, -NO2, F, Cl, Br, I, etc. on the IC50 values towards the inhibition of MNK1 were also reported.
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Affiliation(s)
- S Begum
- a Department of Chemistry , Institute of Technical Education and Research (ITER), Siksha 'O' Anusandhan University , Bhubaneswar , Odisha - 751030 , India
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Li LY, Zhang K, Jiang H, Xie YM, Liao LD, Chen B, Du ZP, Zhang PX, Chen H, Huang W, Jia W, Cao HH, Zheng W, Li EM, Xu LY. Quantitative proteomics reveals the downregulation of GRB2 as a prominent node of F806-targeted cell proliferation network. J Proteomics 2015; 117:145-55. [PMID: 25659534 DOI: 10.1016/j.jprot.2015.01.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Revised: 12/15/2014] [Accepted: 01/18/2015] [Indexed: 02/05/2023]
Abstract
UNLABELLED High-throughput proteomics has successfully identified thousands of proteins as potential therapeutic targets during investigations into mechanisms of drug action. A novel macrolide analog, denoted F806, is a potential antitumor drug. Here, using the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS), we characterize the F806-regulating protein profiles and identify the potential target molecules or pathways of F806 in esophageal squamous cell carcinoma (ESCC) cells. From a total of 1931 quantified proteins, 181 proteins were found to be down-regulated (FDR p-value<0.1, H/L ratio<0.738), and 119 proteins were up-regulated (FDR p-value<0.1, H/L ratio>1.156). Among the down-regulated proteins, we uncovered the over- and under-represented protein clusters in biological process and molecular function respectively by Gene Ontology analysis. Furthermore, down-regulated and up-regulated proteins were significantly enriched in 37 pathways and 60 sub-pathways by bioinformatic analysis (FDR p-value<0.1), while a down-regulated molecule growth factor receptor-bound protein 2 (GRB2) was a prominent node in fourteen cell proliferation-related sub-pathways. We concluded that GRB2 downregulation would be a potential target of F806 in ESCC cells. BIOLOGICAL SIGNIFICANCE This study used SILAC-based quantitative proteomics screen to systematically characterize molecular changes induced by a novel macrolide analog F806 in esophageal squamous cell carcinoma (ESCC) cells. Followed by bioinformatic analyses, signal pathway networks generated from the quantified proteins, would facilitate future investigation into the further mechanisms of F806 in ESCC cells. Notably, it provided information that growth factor receptor-bound protein 2 (GRB2) would be a prominent node in the F806-targeted cell proliferation network.
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Affiliation(s)
- Li-Yan Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Kai Zhang
- Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, PR China
| | - Hong Jiang
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Yang-Min Xie
- Experimental Animal Center, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Lian-Di Liao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Bo Chen
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Ze-Peng Du
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Pi-Xian Zhang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Hong Chen
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Wei Huang
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Wei Jia
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China
| | - Hui-Hui Cao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China
| | - Wei Zheng
- Fujian Provincial Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, PR China.
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, PR China.
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, PR China.
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Jenardhanan P, Mathur PP. Kinases as targets for chemical modulators: Structural aspects and their role in spermatogenesis. SPERMATOGENESIS 2015; 4:e979113. [PMID: 26413395 DOI: 10.4161/21565562.2014.979113] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 10/07/2014] [Accepted: 10/16/2014] [Indexed: 01/18/2023]
Abstract
Protein phosphorylation and de-phosphorylation events are crucial in deciding the fate of cells. They regulate cellular growth, differentiation and cell death, and kinases are the key players of these events. The members of ser/thr kinases and tyrosine kinases form the majority of protein kinase family, exerting their regulatory mechanism in almost all cells. In testis, they impact signal transduction events, regulate all stages of sperm development from mitosis through fertilization. Understanding the function of these kinases at the structural level and studying their interactions with inhibitors can help in understanding the machinery of spermatogenesis. In view of this, we have reviewed some of the prominent kinases that are known to play a role in spermatogenesis. A better understanding of the impacts of kinase inhibition on spermatogenesis should aid in the interpretation of lesions and hopefully further the development of more efficient and potent drug candidates.
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Affiliation(s)
- Pranitha Jenardhanan
- Centre for Bioinformatics; School of Life Sciences; Pondicherry University ; Puducherry, India
| | - Premendu P Mathur
- Centre for Bioinformatics; School of Life Sciences; Pondicherry University ; Puducherry, India ; Department of Biochemistry & Molecular Biology; School of Life Sciences; Pondicherry University ; Puducherry, India ; KIIT University ; Bhubaneshwar, Odisha, India
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Jiang AJ, Jiang G, Li LT, Zheng JN. Curcumin induces apoptosis through mitochondrial pathway and caspases activation in human melanoma cells. Mol Biol Rep 2014; 42:267-75. [PMID: 25262359 DOI: 10.1007/s11033-014-3769-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 09/20/2014] [Indexed: 01/02/2023]
Abstract
Melanoma is the most malignant skin cancer and is highly resistant to chemotherapy and radiotherapy. Curcumin is a component of turmeric, the yellow spice derived from the rhizome of Curcuma longa. It has been demonstrated to modulate multiple cell signaling pathways, including apoptosis, proliferation, angiogenesis and inflammation. In this study, we studied the signaling pathways involved in melanoma cell death after treatment with curcumin using western blotting. Colorimetric assays (MTT) assessed cell viability. Flow cytometry and DNA laddering evaluated cell apoptosis. Fluorescent microscopy was used to evaluate of Hoechst 33342 staining of nuclei. The result demonstrated that curcumin could induce apoptosis and inhibit proliferation in melanoma cells. Curcumin stimulated the expression of pro-apoptotic Bax, and inhibited the activation of anti-apoptotic Mcl-1 and Bcl-2. During curcumin treatment, caspase-8 and Caspase-3 were cleaved in time and dose-dependent manners. Curcumin treatment also altered the expressions of apoptosis associated proteins NF-κB, p38 and p53. Curcumin induced DNA double strand breaks, which were indicated by phosphorylated H2AX. Our data suggested that curcumin could be used as a novel and effective approach for the treatment of melanoma.
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Affiliation(s)
- Ai-Jun Jiang
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, 221002, China
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Erk/MAP kinase signaling pathway and neuroendocrine differentiation of non-small-cell lung cancer. J Thorac Oncol 2014; 9:50-8. [PMID: 24346093 DOI: 10.1097/jto.0000000000000034] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Almost all small-cell lung cancers (SCLC) and carcinoid tumors express neuroendocrine differentiation (NED), and 10% to 20% of non-small-cell lung cancers (NSCLC) are associated with NED. Although distinct clinical features and histology of SCLC and carcinoid tumors are well recognized, the clinical significance and the molecular basis of NED in NSCLC remain unclear. METHODS To explore the potential molecular pathway involved in NED of NSCLC and its clinical relevance, we conducted investigations using an NSCLC cell line (NCI-H157) as a NED induction model, and explored the potential intracellular signal transduction pathways involved in NED of NSCLC. We confirmed our findings using activators versus inhibitors to these signal transduction pathways in vitro. We also performed immunohistochemical stains of phospho-Erk1/2 of lung cancer specimens known to have NED and explored its clinical relevance. RESULTS We discovered that NED of NSCLC was associated with the activation of Erk1/2-mitogen-activated protein kinases (MAPK) signal transduction pathway, and the inhibition of the Akt signal transduction pathway. Using specific activator (Pb) and inhibitors (siRNA-Erk1/2 and U0126) to the Erk1/2-MAP-kinase pathway, as well as the inhibitor (LY294002) to the Akt pathway, we found that Erk1/2-MAP-kinase activation was essential for NED of NCI-H157 cells. Staining of Erk1/2-MAP-kinase pathway revealed a high rate of positivity in NSCLC tumors with NED when compared with other neuroendocrine lung tumors. CONCLUSIONS To our knowledge, our findings are the first to describe the potential involvement of Erk/MAPK signal transduction pathway of NSCLC in the association with NED. Further investigation of the Erk/MAPK signal transduction pathway of NSCLC may yield discoveries in identifying specific molecular targets for the treatment of NSCLC with NED.
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Lin JJ, Su JH, Tsai CC, Chen YJ, Liao MH, Wu YJ. 11-epi-Sinulariolide acetate reduces cell migration and invasion of human hepatocellular carcinoma by reducing the activation of ERK1/2, p38MAPK and FAK/PI3K/AKT/mTOR signaling pathways. Mar Drugs 2014; 12:4783-98. [PMID: 25222667 PMCID: PMC4178498 DOI: 10.3390/md12094783] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 08/11/2014] [Accepted: 08/22/2014] [Indexed: 11/16/2022] Open
Abstract
Cancer metastasis is one of the major causes of death in cancer. An active compound, 11-epi-sinulariolide acetate (11-epi-SA), isolated from the cultured soft coral Sinularia flexibilis has been examined for potential anti-cell migration and invasion effects on hepatocellular carcinoma cells (HCC). However, the molecular mechanism of anti-migration and invasion by 11-epi-SA on HCC, along with their corresponding effects, remain poorly understood. In this study, we investigated anti-migration and invasion effects and the underlying mechanism of 11-epi-SA in HA22T cells, and discovered by trans-well migration and invasion assays that 11-epi-SA provided a concentration-dependent inhibitory effect on the migration of human HCC HA22T cells. After treatment with 11-epi-SA for 24 h, there were suppressed protein levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA) in HA22T cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and metalloproteinase-2 (TIMP-2) were increased in a concentration-dependent manner. Further investigation revealed that 11-epi-SA suppressed the phosphorylation of ERK1/2 and p38MAPK. The 11-epi-SA also suppressed the expression of the phosphorylation of FAK/PI3K/AKT/mTOR pathways.
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Affiliation(s)
- Jen-Jie Lin
- Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91202, Taiwan.
| | - Jui-Hsin Su
- National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan.
| | - Chi-Chu Tsai
- Kaohsiung District Agricultural Improvement Station, Pingtung 900, Taiwan.
| | - Yi-Jen Chen
- Department of Physical Medicine and Rehabilitation, Kaohsiung Medical University Hospital, Kaohsiung 80761, Taiwan.
| | - Ming-Hui Liao
- Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91202, Taiwan.
| | - Yu-Jen Wu
- Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan.
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Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, Oh DY, Liu Y, Redhu S, Steplewski K, Le N. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer 2014; 50:2072-81. [PMID: 24915778 DOI: 10.1016/j.ejca.2014.04.024] [Citation(s) in RCA: 274] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 04/15/2014] [Accepted: 04/28/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. METHODS Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. RESULTS Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. CONCLUSIONS The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.
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Affiliation(s)
- Jeffrey R Infante
- Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, United States.
| | | | - Joon Oh Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chung-Pin Li
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Max E Scheulen
- Department of Internal Medicine, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | | | - Do-Youn Oh
- Seoul National University Hospital, Seoul, South Korea
| | - Yuan Liu
- GlaxoSmithKline, Collegeville, PA, United States
| | - Suman Redhu
- GlaxoSmithKline, Collegeville, PA, United States
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Li Y, Lu X, Qi H, Li X, Xiao X, Gao J. Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and suppression of ERK1/2 MAPK in HeLa cells. J Pharmacol Sci 2014; 125:202-10. [PMID: 24881958 DOI: 10.1254/jphs.14017fp] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been demonstrated to induce apoptosis in various tumors. The aim of the present study was to elucidate the molecular mechanisms of UA-induced apoptosis in HeLa cells. Here, we reported that UA induced apoptosis through the mitochondrial intrinsic pathway in HeLa cells, as shown by release of cytosol cytochrome c, activation of caspase-9 and -3, reduction of Bcl-2 and Bcl-xL, and increase of Bax and Bak. UA down-regulated the phosphorylation of ERK1/2 and p38, whereas phosphorylation of JNK was unchanged. The roles of ERK1/2 and p38 were further confirmed using the ERK1/2 inhibitor (U0126) and p38 inhibitor (SB203580). U0126 markedly increased UA-induced the Bax/Bcl-2 ratio, the increase of cytosol cytochrome c, and the levels of cleaved caspase-3, but SB203580 had little effects on the above characters, suggesting the ERK1/2 signaling pathway is required for apoptosis. Furthermore, UA up-regulated DUSP 1, 2, 4, 5, 6, 7, 9, and 10 mRNA expressions, which may be a clue for the role of dephosphorylation of ERK1/2 and p38. These data suggested that the apoptotic mechanism of UA treatment in HeLa cells was through the mitochondrial intrinsic pathway and closely associated with the suppression of the ERK1/2 signaling pathway.
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Affiliation(s)
- Yanhong Li
- Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, China
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Lin J, Chen Y, Cai Q, Wei L, Zhan Y, Shen A, Sferra TJ, Peng J. Scutellaria Barbata D Don Inhibits Colorectal Cancer Growth via Suppression of Multiple Signaling Pathways. Integr Cancer Ther 2014; 13:240-248. [PMID: 24231788 DOI: 10.1177/1534735413508811] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The pathogenic mechanisms underlying cancer development are complex and heterogeneous, involving multiple cellular signaling transduction pathways that usually function redundantly. In addition, crosstalk between these pathways generates a complicated and robust signaling network that is regulated by compensatory mechanisms. Given the complexity of cancer pathogenesis and progression, many of the currently used antitumor agents, which typically target a single intracellular pathway, might not always be effective on complex tumor systems. Moreover, long-term use of these agents often generates drug resistance and toxicity against normal cells. Therefore, the development of novel anticancer chemotherapies is urgently needed.Scutellaria barbataD Don (SB) is a medicinal herb that has long been used in China to treat various types of cancer. We previously reported that the ethanol extract of SB (EESB) is able to induce colon cancer cell apoptosis, inhibit cell proliferation and tumor angiogenesis via modulation of several pathways, including Hedgehog, Akt, and p53. To further elucidate the precise mechanisms of SB's antitumor activity, using a colorectal cancer (CRC) mouse xenograft model in the present study, we evaluated the therapeutic efficacy and molecular mechanisms of EESB against tumor growth. We found that EESB reduced tumor volume and tumor weight but had no effect on body weight gain in CRC mice, demonstrating that EESB could inhibit colon cancer growth in vivo without apparent adverse effect. In addition, EESB treatment could significantly suppress the activation of several CRC-related pathways, including STAT3, Erk, and p38 signalings in tumor tissues, and alter the expression of multiple critical target genes such as Bcl-2, Bax, Cyclin D1, CDK4, and p21. These molecular effects lead to the induction of cancer cell apoptosis and inhibition of cell proliferation. Our findings demonstrate that SB possesses a broad range of antitumor activities because of its ability to affect multiple intracellular targets.
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Affiliation(s)
- Jiumao Lin
- Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Youqin Chen
- Case Western Reserve University School of Medicine, Rainbow Babies & Children's Hospital, Cleveland, OH, USA
| | - Qiaoyan Cai
- Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Lihui Wei
- Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Youzhi Zhan
- Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Aling Shen
- Fujian University of Traditional Chinese Medicine, Fujian, China
| | - Thomas J Sferra
- Case Western Reserve University School of Medicine, Rainbow Babies & Children's Hospital, Cleveland, OH, USA
| | - Jun Peng
- Fujian University of Traditional Chinese Medicine, Fujian, China
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Ryu DS, Kim SH, Kwon JH, Lee DS. Orostachys japonicus induces apoptosis and cell cycle arrest through the mitochondria-dependent apoptotic pathway in AGS human gastric cancer cells. Int J Oncol 2014; 45:459-69. [PMID: 24789703 DOI: 10.3892/ijo.2014.2404] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 04/07/2014] [Indexed: 11/06/2022] Open
Abstract
We investigated the anticancer mechanisms of the ethylacetate (EtOAc) fraction from Orostachys japonicus in human gastric cancer (AGS) cells. Flow cytometric analysis revealed that the number of total apoptotic cells following treatment with the EtOAc fraction increased in a dose-dependent manner. In the cell cycle analyses, the EtOAc fraction increased the peak in the sub-G1, indicating apoptosis, and in the G₂/M phases in a dose-dependent manner. In the RT-PCR analysis, the expression of cyclin-dependent kinase 1 (CDK 1) and cyclin B1 decreased in a dose- and time-dependent manner. The results of western blotting revealed that the protein levels of p53, cytochrome c, and cleaved caspase-3, -8 and -9 proteins increased and those of B cell lymphoma-2 (bcl-2) and pro-caspase-3, -8 and -9 proteins decreased in a dose- and time-dependent manner, whereas the levels of bcl-2-associated x protein (bax) remained unchanged. Furthermore, the changes in the levels of pro-caspase-3, -8 and -9 and cleaved caspase-3, -8 and -9 were abolished by the pan-caspase inhibitor Z-VAD-FMK. In addition, phosphorylation of p38 and JNK increased in a time-dependent manner. These results, for the first time, provide an understanding of the potential anticancer activity of the O. japonicus, which functions through the induction of apoptosis and cell cycle arrest.
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Affiliation(s)
- Deok-Seon Ryu
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Gyungnam 621-749, Republic of Korea
| | - Seon-Hee Kim
- Department of Smart Foods and Drugs, Graduate School of Inje University, Gimhae, Gyungnam 621-749, Republic of Korea
| | - Ji-Hae Kwon
- Department of Smart Foods and Drugs, Graduate School of Inje University, Gimhae, Gyungnam 621-749, Republic of Korea
| | - Dong-Seok Lee
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Gyungnam 621-749, Republic of Korea
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The apoptotic effect of D Rhamnose β-hederin, a novel oleanane-type triterpenoid saponin on breast cancer cells. PLoS One 2014; 9:e90848. [PMID: 24603880 PMCID: PMC3946269 DOI: 10.1371/journal.pone.0090848] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Accepted: 02/04/2014] [Indexed: 01/09/2023] Open
Abstract
There is growing interest in development of natural products as anti-cancer and chemopreventive agents. Many triterpenoids have been proved as potential agents for chemoprevention and therapy of breast cancer. Ginsenosides from ginseng, which mostly belong to dammarane-type triterpenoids, have gained great attention for their anti-breast cancer activity with diverse mechanisms. However, studies of other kinds of triterpenoid saponins on breast cancer are limited. Previously, we purified and identified a novel oleanane-type triterpene saponin named D Rhamnose β-hederin (DRβ-H) from Clematis ganpiniana, a Chinese traditional anti-tumor herb. In the present study, DRβ-H showed strong inhibitory activity on the growth of various breast cancer cells and induced apoptosis in these cells. DRβ-H inhibited PI3K/AKT and activated ERK signaling pathway. PI3K inhibitor LY294002 synergistically enhanced DRβ-H-induced apoptosis whereas MEK inhibitor U0126 reduced the apoptosis rate. Moreover, DRβ-H regulated the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins. Furthermore, DRβ-H induced depolarization of mitochondrial membrane potential which released Apaf-1 and Cytochrome C from the inter membrane space into the cytosol, where they promoted caspase-9 and caspase-3 activation. This is the first report on the pro-apoptotic effects of DRβ-H, a novel oleanane-type triterpenoid saponin, on breast cancer cells and its comprehensive apoptosis pathways. It implied that oleanane-type triterpenoid saponin DRβ-H could be a promising candidate for chemotherapy of breast cancer.
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Vitagliano O, Addeo R, D’Angelo V, Indolfi C, Indolfi P, Casale F. The Bcl-2/Bax and Ras/Raf/MEK/ERK signaling pathways: implications in pediatric leukemia pathogenesis and new prospects for therapeutic approaches. Expert Rev Hematol 2014; 6:587-97. [DOI: 10.1586/17474086.2013.827415] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Schwartz TL, Mogal H, Papageorgiou C, Veerapong J, Hsueh EC. Metaplastic breast cancer: histologic characteristics, prognostic factors and systemic treatment strategies. Exp Hematol Oncol 2013; 2:31. [PMID: 24499560 PMCID: PMC3832232 DOI: 10.1186/2162-3619-2-31] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 11/08/2013] [Indexed: 02/06/2023] Open
Abstract
Metaplastic breast cancer (MBC) is a rare subtype of invasive breast cancer that tends to have an aggressive clinical presentation as well as a variety of distinct histologic designations. Few systemic treatment options are available for MBC, as it has consistently shown a suboptimal response to standard chemotherapy regimens. These characteristics result in a worse overall prognosis for patients with MBC compared to those with standard invasive breast cancer. Due to its rarity, data focusing on MBC is limited. This review will discuss the clinical presentation, breast imaging findings, histologic and molecular characteristics of MBC as well as potential future research directions.
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Affiliation(s)
- Theresa L Schwartz
- Department of Surgery, Saint Louis University School of Medicine, 3635 Vista Avenue-DT 3rd floor, Saint Louis, MO 63110, USA.
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Bai LY, Weng JR, Hu JL, Wang D, Sargeant AM, Chiu CF. G15, a GPR30 antagonist, induces apoptosis and autophagy in human oral squamous carcinoma cells. Chem Biol Interact 2013; 206:375-84. [DOI: 10.1016/j.cbi.2013.10.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 09/14/2013] [Accepted: 10/14/2013] [Indexed: 01/11/2023]
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Lin J, Chen Y, Wei L, Shen A, Sferra TJ, Hong Z, Peng J. Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways. Int J Oncol 2013; 43:1235-1243. [PMID: 23900560 DOI: 10.3892/ijo.2013.2040] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/17/2013] [Indexed: 11/06/2022] Open
Abstract
The development of colorectal cancer (CRC) is strongly correlated with the aberrant activation of multiple intracellular signaling transduction cascades including STAT3, ERK, JNK and p38 pathways which usually function redundantly. In addition, crosstalk between these pathways forms a complicated signaling network that is regulated by compensatory mechanisms. Therefore, most of the currently used and single-target-based antitumor agents might not always be therapeutically effective. Moreover, long-term use of these agents often generates drug resistance. These problems highlight the urgent need for the development of novel anticancer chemotherapies. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used for the clinical treatment of CRC. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its tumoricidal activity are not well understood. In the present study, using CRC mouse xenograft model and the HT-29 human colon carcinoma cell line, we evaluated the efficacy of UA against tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms. We found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation. These data demonstrate that UA possesses a broad range of anticancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment.
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Affiliation(s)
- Jiumao Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
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