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  • br Central glial activation mediates cancer induced pain in

    2020-08-18


    Central glial activation mediates cancer-induced pain in a rat facial cancer model.
    C.M. Kopruszinski et al.
    capsaicin-induced TRPV1 currents via the endothelin A receptor. Experimental Biology and Medicine (Maywood, NJ), 231(6), 1161–1164.
    (2015). Behavioral and neurochemical analysis of ongoing bone cancer pain in rats.
    www.neoplasia.com
    Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability
    Monika Raab*, Mourad Sanhaji*, Shengtao Zhou†, Franz Rödel‡, §, Ahmed El-Balat*, Sven Becker* and Klaus Strebhardt*, §
    * Department of Gynecology, Goethe-University, Frankfurt am Main; †State Key Laboratory of Biotherapy, Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, 610041, P. R. China;
    ‡Department of Radiotherapy and Oncology, Goethe University; §German Cancer Consortium (DKTK) / German Cancer Research Center, partner site, Frankfurt a. M.
    Abstract
    Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor HC030031 to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
    Introduction
    Epithelial ovarian cancer (EOC) is a leading cause of cancer death in women worldwide [1,2]. Microtubule targeting inhibitors like paclitaxel represent one of the most important and promising classes of cancer drugs used in the treatment of ovarian, breast, and lung cancer [3,4]. The Gynecological Cancer Inter Group recommended in 2005 as standard of care for first-line chemotherapy the intravenous adminis-tration of paclitaxel in combination with carboplatin every 3 weeks for 6 cycles [5,6]. Approximately two-thirds of ovarian cancer patients will respond to a therapeutical strategy that starts with surgical debulking and is followed by a paclitaxel/carboplatin-including chemotherapy, but tumor recurrence occurs in most patients at a median of 15 months from initial diagnosis [7–9] often followed by chemoresistance. In HC030031 addition to its role as first-line agent in a combined therapy, paclitaxel is a promising agent for relapsed platinum-refractory epithelial ovarian 
    cancer. However, the response to microtubule targeting agents is highly variable, which might interfere with clinical efficiency [10–12]. Importantly, while certain side effects like myelosuppression are manageable, more problematic are the peripheral neuropathies induced by inhibiting microtubule dynamics in nondividing cells [13].
    Abbreviations: CIN, chromosomal instability; APC/C, Anaphase-Promoting Complex; EOC, epithelial ovarian cancer; PLK1, polo-like kinase 1
    Address all correspondence to: Prof. Dr. K. Strebhardt, Department of Gynecology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main. Received 17 January 2019; Accepted 29 January 2019
    © 2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
    Paclitaxel treatment arrests cells in mitosis due to the presence of a small number of unattached kinetochores [14], which have not made stable attachments to microtubules, thereby activating the spindle assembly checkpoint (SAC) that delays mitotic progression by inhibiting the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C) [15–17]. The APC/C represents a highly complex ubiquitin ligase machinery. At different cell cycle stages the activator proteins CDH1 and CDC20 associate with certain subunits of the APC/C to stimulate APC/C-dependent ubiquitination of substrates and their subsequent proteolysis by the 26S proteasome [18]. Furthermore, the exit from mitosis and the onset of anaphase require CDC20-dependent ubiquitination of APC/C substrates including securin and mitotic cyclins. Cyclin B1 is one of the most important substrates of the APC/C that plays a key role for the timing of the mitotic arrest.