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Preclinical and clinical development of new progesterone receptor antagonists with high receptor specificity for breast cancer treatment
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
J. Hoffmann, H. Hess-Stumpp, R. B. Lichtner, U. Fuhrmann, G. Siemeister, M. R. Schneider
Recent studies implicate growth arrest accompanied by up-regulation of p21 not only in inhibiting proliferation but also in promoting differentiation12. Furthermore, this cyclin-dependent kinase inhibitor has been postulated to be a key intermediary protein in the pathway that determines whether cells proliferate or differentiate13. The promoter of p21 lacks a canonical progesterone element, and thus is activated by progesterone through a novel mechanism that involves interactions between progesterone receptors and CPB/p300, similarly to other agents (phorbol esters, buryrate, BRCA-1 and transforming growth factor ß(TGF-ß)14.
Participation of Cytokines and Growth Factors in Biliary Epithelial Proliferation and Mito-Inhibition during Ductular Reactions
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Anthony J. Demetris, J.G. Lunz, Vladimir Subbotin, Tong Wu, Isao Nozaki, Sarah Contrucci, Xia Yin
We recently examined in mice, the BEC expression of p21 and a closely related cyclin dependent kinase inhibitor, p27, up to 12 weeks after BDL (Lunz, submitted). The BEC of normal liver do not express p21, whereas p27 is universally expressed in nearly all non-proliferating BEC. Using the mouse BDL model, we found that BEC p21 expression was induced under two circumstances: 1) immediately after BEC proliferation during the post-mitotic period (Lunz, submitted Fig. 6), similar to hepatocytes following partial hepatectomy;174–175 and 2) under conditions of severe stress, where it is thought to play a primary mito-inhibitory function (Lunz, submitted). In cholangiocarcinomas, p21 expression is direcdy proportional to Ki67 staining,176,177 whereas in other nonneoplastic biliary tract diseases such as primary biliary cirrhosis increased BEC expression of p21178 has been linked to BEC stress and apoptosis.178 In contrast, the ubiquitous expression of p27 in BEC of normal untreated mice decreases in direct proportion to increases in BEC proliferation. This suggests that p27 is a more important contributor to the GO cell cycle phase in normal physiology, whereas p21 is more frequently involved in pathophysiologic conditions. In cholangiocarcinomas, p27 is also inversely related to Ki67 labeling.176,177
Zearalenone: Insights into New Mechanisms in Human Health
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Cornelia Braicu, Alina Andreea Zimta, Ioana Berindan-Neagoe
The carcinogenic properties of ZEA and its metabolites extend to the downregulation of tumor suppressor gene p53 and upregulation of the DNMT1, which encodes an enzyme with the property of setting the pattern of methylated DNA. It also seems that these effects have a greater impact on the cancerous cells than on the normal mammary cells of different types [77]. The reduction of apoptosis is also due to the upregulation of BCL-2, one of the most important anti-apoptotic proteins [78]. Downregulation of a cyclin-dependent kinase inhibitor (p21Cip1) was reported only at low doses of α-zearalenol. However, at high concentrations, α-zearalenol has the opposite effect on cancerous cells, by upregulating p53 [79]. As the human exposure is in low doses over a longer period of time, the results are of increasing concern for women's health.
CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors
Published in OncoImmunology, 2022
Inken Salewski, Julia Henne, Leonie Engster, Paula Krone, Bjoern Schneider, Caterina Redwanz, Heiko Lemcke, Larissa Henze, Christian Junghanss, Claudia Maletzki
To improve outcomes, ICIs should be combined with other (targeted) agents. A very attractive option is the selective cyclin-dependent kinase 4/6 inhibitor (CDKI) abemaciclib.10 Abemaciclib stops the cell cycle at G1, induces swollen and dysfunctional lysosomes, and triggers apoptosis/necrosis in tumor cells.11–13 This CDK4/6 inhibitor is currently approved for treatment of both early and advanced/metastatic breast cancer, however, more immunogenic tumor types, such as dMMR-related cancers, should be considered as well. The rationale for this is based on the increasing body of evidence that abemaciclib stimulates antitumor immune responses by inducing an “inflamed” microenvironment finally contributing to T cell activation and improved T cell function.14–17 Actually, a recent study reported transformation of CD8+ T cells into memory cells upon CDK4/6 inhibition to expand the long-term immunity and efficacy of the cancer treatment – an effect frequently seen after ICI treatment.18 CDK blockade may thus become an interesting option for dMMR patients not eligible for ICI treatment. The notion that many patients harbor pre-formed antitumoral immune responses that can be re-activated (or boosted) by immunotherapy additionally argues in favor of using immune-modulating CDKIs for treatment of dMMR-related malignancies.19–21
Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hyun Seung Ban, Yoshikazu Uto, Hiroyuki Nakamura
The Research Institute of Fox Chase Cancer Center disclosed drug combinations comprising a cyclin-dependent kinase inhibitor (CDKI) (Kenpaullone, PKC-412, palbociclib) and HSP90 inhibitors (e.g., tanespimycin and luminespib), and methods for treating cancer. The inventors have previously reported that CDKI stabilizes HIF-1α through direct phosphorylation of its Ser668 residue in a Von Hippel-Lindau (VHL)-independent manner both under hypoxia and under normoxia [25]. In addition, HSP90 is also known to be a VHL-independent HIF-1α stabilizer that has been correlated with adverse prognosis and has been recognized as a therapeutic target in cancer [26]. Both investigations have led to the current patent application, indicating that crosstalk between CDK1-mediated and HSP90-mediated HIF-1α stabilization could be a therapeutic target.
Bazedoxifene increases the proliferation of human arterial endothelial cells but does not affect the expression of cyclins A, B, and D1 and of p27Kip1
Published in Gynecological Endocrinology, 2021
Darya Dudenko, Raúl Gómez, Miguel-Ángel García-Pérez, Juan J. Tarín, Antonio Cano
Endothelial damage is considered a first step in the initiation of atherosclerosis [9]. Surprisingly, there is no information on the direct endothelial actions of BZA, only general studies on the vascular wall of rodents [10, 11]. Endothelial proliferation is key for cellular repair. In the present study we used an improved cellular model in which endothelial cells from human umbilical arteries replaced the usual human umbilical vein endothelial cells (HUVEC). We investigated the effect of BZA, or BZA combined with estradiol (E2), on arterial cellular proliferation. Moreover, we investigated whether the effects were associated with changes in the expression of a representative group of a family of proteins directly involved in the cell cycle [12], the cyclins A, B, D1, and p27Kip1, one cyclin dependent kinase inhibitor.