Development of Pin1 Inhibitors and their Potential as Therapeutic Agents

2020 ◽  
Vol 27 (20) ◽  
pp. 3314-3329 ◽  
Author(s):  
Yusuke Nakatsu ◽  
Yasuka Matsunaga ◽  
Koji Ueda ◽  
Takeshi Yamamotoya ◽  
Yuki Inoue ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Malignant Tumors ◽  
Therapeutic Agents ◽  
Prolyl Isomerase ◽  
Trans Conformation ◽  
Anti Cancer ◽  
Pin1 Inhibitor ◽  
Degree Of Malignancy ◽  
Highly Correlated ◽  
Deficient Mice

<P>The prolyl isomerase Pin1 is a unique enzyme, which isomerizes the cis-trans conformation between pSer/pThr and proline and thereby regulates the function, stability and/or subcellular distribution of its target proteins. Such regulations by Pin1 are involved in numerous physiological functions as well as the pathogenic mechanisms underlying various diseases. Notably, Pin1 deficiency or inactivation is a potential cause of Alzheimer’s disease, since Pin1 induces the degradation of Tau. In contrast, Pin1 overexpression is highly correlated with the degree of malignancy of cancers, as Pin1 controls a number of oncogenes and tumor suppressors. Accordingly, Pin1 inhibitors as anti-cancer drugs have been developed. Interestingly, recent intensive studies have demonstrated Pin1 to be responsible for the onset or development of nonalcoholic steatosis, obesity, atherosclerosis, lung fibrosis, heart failure and so on, all of which have been experimentally induced in Pin1 deficient mice. <P> In this review, we discuss the possible applications of Pin1 inhibitors to a variety of diseases including malignant tumors and also introduce the recent advances in Pin1 inhibitor research, which have been reported.</P>

scholarly journals Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuming Zhao ◽  
Dengyang Zhang ◽  
Yao Guo ◽  
Bo Lu ◽  
Zhizhuang Joe Zhao ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Malignant Tumors ◽  
Wnt Signaling Pathway ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Functional Features ◽  
Survival Signaling ◽  
Preclinical And Clinical Studies ◽  
Canonical Wnt

Receptor tyrosine kinase ROR1 plays an essential role in embryogenesis and is overexpressed in many types of malignant tumors. Studies have demonstrated that it plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway. Antibody-based immunotherapies targeting ROR1 have been developed and evaluated in preclinical and clinical studies with promising outcomes. However, small molecule inhibitors targeting ROR1 are underappreciated because of the initial characterization of ROR1 as a peusdokinase. The function of ROR1 as a tyrosine kinase remains poorly understood, although accumulating evidence have demonstrated its intrinsic tyrosine kinase activity. In this review, we analyzed the structural and functional features of ROR1 and discussed therapeutic strategies targeting this kinase.

The main strategies for tuning BODIPY fluorophores into photosensitizers

2020 ◽  
Vol 24 (05n07) ◽  
pp. 603-635 ◽  
Author(s):  
Jun Wang ◽  
Qingbao Gong ◽  
Long Wang ◽  
Erhong Hao ◽  
Lijuan Jiao
Keyword(s):  
Singlet Oxygen ◽  
Fluorescent Dyes ◽  
Malignant Tumors ◽  
Therapeutic Agents ◽  
Invasive Technique ◽  
Generation Efficiency ◽  
Oxygen Generation ◽  
Singlet Oxygen Generation ◽  
Cancer Tumor ◽  
Dual Imaging

Photodynamic therapy (PDT) is a minimally invasive technique for the treatment of target malignant tumors via the generation of highly reactive singlet oxygen species. PDT treatment of cancer/tumor tissues greatly relies on the development of suitable stable, highly specific and efficient photosensitizers. BODIPY (Boron dipyrromethene) derivatives, as a class of well-developed, versatile fluorescent dyes, has emerged as a new class of PDT agents over the past decade. Many elegant strategies have been developed to enhance the singlet oxygen generation efficiency and the cancer/tumor cell selectivity of BODIPY-based photosensitizers to improve the therapeutic outcomes as well as to minimize the side effects. Many of the currently reported BODIPY-based photosensitizers are valuable dual imaging and therapeutic agents, which can efficiently generate singlet oxygen for PDT and emit fluorescence for in vivo imaging. Although the currently approved PDT agents used for clinical trials do not feature BODIPYs, this situation is expected to change. In this review, we provide an overview of the various strategies that have been used to improve the singlet oxygen generation efficiency for tuning BODIPY fluorophores into photosensitizers and dual imaging/therapeutic agents. Their photophysical properties and photocytotoxic activity including the absorption/emission wavelengths, the singlet oxygen generation efficiency ([Formula: see text] and the half maximal inhibitory concentration [Formula: see text] of these currently reported photosensitizers are summarized. We believe these newly developed BODIPY-based photosensitizers will broaden current concepts of strategies for PDT agent design, and promise to make an important contribution to the diagnosis and therapeutics for the treatment of cancer.

scholarly journals Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer

Medicines ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. 17 ◽  
Author(s):  
Maryam Nakhjavani ◽  
Jennifer E Hardingham ◽  
Helen M Palethorpe ◽  
Yoko Tomita ◽  
Eric Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Metastatic Breast ◽  
Therapeutic Agents ◽  
Ginsenoside Rg3 ◽  
Cancer Models ◽  
Anti Cancer ◽  
Ginseng Plant

Breast cancer is still one of the most prevalent cancers and a leading cause of cancer death worldwide. The key challenge with cancer treatment is the choice of the best therapeutic agents with the least possible toxicities on the patient. Recently, attention has been drawn to herbal compounds, in particular ginsenosides, extracted from the root of the Ginseng plant. In various studies, significant anti-cancer properties of ginsenosides have been reported in different cancers. The mode of action of ginsenoside Rg3 (Rg3) in in vitro and in vivo breast cancer models and its value as an anti-cancer treatment for breast cancer will be reviewed.

scholarly journals Design of Anticancer 2,4-Diaminopyrimidines as Novel Anoctamin 1 (ANO1) Ion Channel Blockers

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5180
Author(s):  
Taewoo Kim ◽  
Sinyoung Cho ◽  
Haejun Oh ◽  
Joonseong Hur ◽  
Haedong Kim ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
A549 Cells ◽  
Channel Blockers ◽  
Anoctamin 1 ◽  
Ion Channel Blockers ◽  
Anti Cancer ◽  
Small Set ◽  
Privileged Scaffold ◽  
Prostate Cancers ◽  
Dose Dependent

Pyrimidine is a privileged scaffold in many synthetic compounds exhibiting diverse pharmacological activities, and is used for therapeutic applications in a broad spectrum of human diseases. In this study, we prepared a small set of pyrimidine libraries based on the structure of two hit compounds that were identified through the screening of an in-house library in order to identify an inhibitor of anoctamin 1 (ANO1). ANO1 is amplified in various types of human malignant tumors, such as head and neck, parathyroid, and gastrointestinal stromal tumors, as well as in breast, lung, and prostate cancers. After initial screening and further structure optimization, we identified Aa3 as a dose-dependent ANO1 blocker. This compound exhibited more potent anti-cancer activity in the NCI-H460 cell line, expressing high levels of ANO1 compared with that in A549 cells that express low levels of ANO1. Our results open a new direction for the development of small-molecule ANO1 blockers composed of a pyrimidine scaffold and a nitrogen-containing heterocyclic moiety, with drug-like properties.

scholarly journals Polymeric Co-Delivery Systems in Cancer Treatment: An Overview on Component Drugs’ Dosage Ratio Effect

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1035 ◽  
Author(s):  
Jiayi Pan ◽  
Kobra Rostamizadeh ◽  
Nina Filipczak ◽  
Vladimir Torchilin
Keyword(s):  
Cancer Therapy ◽  
Cancer Treatment ◽  
Therapeutic Agent ◽  
Polymeric Nanoparticles ◽  
Therapeutic Agents ◽  
Delivery Systems ◽  
Individual Therapy ◽  
Multiple Factors ◽  
Therapeutic Outcomes ◽  
Anti Cancer

Multiple factors are involved in the development of cancers and their effects on survival rate. Many are related to chemo-resistance of tumor cells. Thus, treatment with a single therapeutic agent is often inadequate for successful cancer therapy. Ideally, combination therapy inhibits tumor growth through multiple pathways by enhancing the performance of each individual therapy, often resulting in a synergistic effect. Polymeric nanoparticles prepared from block co-polymers have been a popular platform for co-delivery of combinations of drugs associated with the multiple functional compartments within such nanoparticles. Various polymeric nanoparticles have been applied to achieve enhanced therapeutic efficacy in cancer therapy. However, reported drug ratios used in such systems often vary widely. Thus, the same combination of drugs may result in very different therapeutic outcomes. In this review, we investigated polymeric co-delivery systems used in cancer treatment and the drug combinations used in these systems for synergistic anti-cancer effect. Development of polymeric co-delivery systems for a maximized therapeutic effect requires a deeper understanding of the optimal ratio among therapeutic agents and the natural heterogenicity of tumors.

scholarly journals Establishment and Characterization of a Human Adrenocortical Carcinoma Xenograft Model*

Endocrinology ◽  
2000 ◽  
Vol 141 (9) ◽  
pp. 3165-3171 ◽  
Author(s):  
Armelle Logié ◽  
Philippe Boudou ◽  
Liliane Boccon-Gibod ◽  
Eric Baudin ◽  
Gilles Vassal ◽  
...  
Keyword(s):  
Cell Line ◽  
Adrenocortical Carcinoma ◽  
Malignant Tumors ◽  
Xenograft Model ◽  
Therapeutic Agents ◽  
Therapeutic Trials ◽  
Igf System ◽  
Suitable Animal Model ◽  
17 Hydroxyprogesterone ◽  
Adrenocortical Carcinomas

Abstract Adrenocortical carcinomas are rare malignant tumors. They have a poor prognosis, as they are often diagnosed late and are usually resistant to chemotherapy. The lack of a suitable animal model for these tumors has been a major obstacle to the evaluation of new therapeutic agents. The aim of this study was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for future therapeutic trials. This cell line was sc injected (6 × 106 cells) into nude mice (n = 20). Solid tumors were locally measurable after 45 days at 90% of the inoculation sites. The xenografts were similar histologically to the original adrenocortical carcinoma from which the cell line was derived. The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system[ overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarly to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone,Δ 4-androstenedione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts produced all three class of steroids, with the preferential production of androgens of the Δ4 pathway. The H295R xenograft model is a good model of human adrenocortical carcinoma, as it mimics dysregulation of the IGF system usually found in these tumors. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.

scholarly journals Expressions of Endocan in Patients with Meningiomas and Gliomas

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Pinar Atukeren ◽  
Ahmad Kunbaz ◽  
Okan Turk ◽  
Rahsan Kemerdere ◽  
Mustafa Onur Ulu ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Immunosorbent Assay ◽  
Malignant Tumors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Steady Increase ◽  
Low Grade ◽  
High Grade ◽  
Control Brain ◽  
Tumor Group ◽  
Degree Of Malignancy

Objective. Endocan has been shown to be a marker for several cancers and may show degree of malignancy. The aim of this study is to assess tissue levels of endocan in common brain tumors, namely, meningiomas, low-grade gliomas (LGGs), and high-grade gliomas (HGGs).Patients and Methods. Endocan was assayed by commercially available enzyme linked immunosorbent assay (ELISA) kits in a total of 50 brain tumors (20 meningiomas, 19 LGGs, and 20 HGGs) and 15 controls. The results were compared to control brain tissues.Results. Each tumor group showed significant higher levels of endocan compared to controls (p<0.05). In addition, endocan levels showed steady increase from the least (meningiomas) to the most (HGGs) malignant tumors and positive correlation was noted between the degree of malignancy and endocan level (p=0.0001).Conclusion. Endocan, a vital molecule for angiogenesis, is expressed in common brain tumors and results suggest that endocan could be a marker for malignancy.

Sign in / Sign up

Export Citation Format

Share Document