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Kaili Qin, Kailin Chen, Wenpeng Zhao, Xiangcong Zhao, Jing Luo, Qun Wang, Chong Gao, Xiaofeng Li, Caihong Wang
Objective: Rheumatoid arthritis (RA) multidrug resistance is associated with P-glycoprotein (P-gp) overexpression. We investigated the effects of methotrexate (MTX) alone and combined with 4-hydroperoxycyclophosphamide (4-HC) on P-gp expression in fibroblast-like synoviocytes (FLSs) from patients with RA and examined the signaling pathway involved. Methods: RA-FLSs were treated with MTX, MTX + 4-HC, AG490 + MTX, or AG490 + MTX + 4-HC for 72 h. Proliferation inhibition rates were determined by MTT assay; P-gp expression was measured by flow cytometry and real-time polymerase chain reaction (RT-PCR); JAK2 and STAT3 were measured by RT-PCR and cell-based ELISA to assess STAT3 signaling...
2018: Journal of Immunology Research
F Horicks, G Van Den Steen, C Gervy, H J Clarke, I Demeestere
STUDY QUESTION: Does fertility preservation using gonadotrophin-releasing hormone (GnRH) analogues during chemotherapy act through a direct effect on the ovary or through inhibition of FSH secretion? SUMMARY ANSWER: The absence of FSH in vivo and the direct exposition of ovarian follicles to GnRH analogues in vitro did not prevent chemotherapy-induced ovarian damage. WHAT IS KNOWN ALREADY: The potential mechanisms of action of GnRH analogues in protecting ovaries against chemotherapy damage remain poorly understood...
April 1, 2018: Molecular Human Reproduction
Malgorzata Opydo-Chanek, Katarzyna Śladowska, Kamil Blicharski, Jaromir Mikeš, Peter Fedoročko, Ulf Niemeyer, Lidia Mazur
BACKGROUND/AIM: The oxazaphosphorines, ifosfamide and cyclophosphamide, represent a class of alkylating agents. The aim of the present in vitro study was to compare antileukemic activity of 4-hydroperoxyifosfamide (4-OOH-IF) and 4-hydroperoxycyclophosphamide (4-OOH-CP). MATERIALS AND METHODS: The experiments were performed on MOLT-4 and ML-1 cells. The research was conducted using flow cytometry fluorescein diacetate/propidium iodide (PI), fluorescein-conjugated annexin V/PI, CaspGLOW Red Active Caspase-8 and -9, CellEvent™ Caspase-3/7 Green assays, and tetramethylrhodamine ethyl ester test...
November 2017: Anticancer Research
Benigno C Valdez, Moustapha Hassan, Borje S Andersson
Drug interactions may dictate the failure or success of a treatment. Patients undergoing hematopoietic stem cell transplantation (HSCT) are exposed to various types of drugs, and understanding how these drugs interact is of the utmost importance. The pharmacokinetics of busulfan, melphalan, and cyclophosphamide, drugs commonly used for HSCT, are known to be affected by a variety of other drugs with differing molecular structures. We hypothesized that these structurally unrelated drugs affect the transport of DNA-alkylating agents...
August 2017: Experimental Hematology
Maura Gasparetto, Shanshan Pei, Mohammad Minhajuddin, Nabilah Khan, Daniel A Pollyea, Jason R Myers, John M Ashton, Michael W Becker, Vasilis Vasiliou, Keith R Humphries, Craig T Jordan, Clayton A Smith
Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is high in hematopoietic stem cells and functions in part to protect stem cells from reactive aldehydes and other toxic compounds. In contrast, we found that approximately 25% of all acute myeloid leukemias expressed low or undetectable levels of ALDH1A1 and that this ALDH1A1- subset of leukemias correlates with good prognosis cytogenetics. ALDH1A1- cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide...
June 2017: Haematologica
Yechezkel Lande, Benjamin Fisch, Abraham Tsur, Jacob Farhi, Roni Prag-Rosenberg, Avi Ben-Haroush, Gania Kessler-Icekson, Muayad A Zahalka, Susan M Ludeman, Ronit Abir
How chemotherapy affects dormant ovarian primordial follicles is unclear. The 'burnout' theory, studied only in mice, suggests cyclophosphamide enhances primordial follicle activation. Using 4-hydroperoxycyclophosphamide (4hc) and phosphoramide mustard (PM), this study assessed how the active cyclophosphamide metabolites 4-hydroxycyclophosphamide (4-OHC) and PM, affect human primordial follicles. Frozen-thawed human ovarian samples were sliced and cultured with basic culture medium (cultured controls) or with 4hc/PM (3 µmol/l/10 µmol/l) (treated samples) for 24-48 h...
January 2017: Reproductive Biomedicine Online
Annamária Marton, Erzsébet Kúsz, Csongor Kolozsi, Vilmos Tubak, Giuseppe Zagotto, Krisztina Buzás, Luigi Quintieri, Csaba Vizler
BACKGROUND/AIM: Constitutive activation of nuclear factor kappa-B (NFĸB) is a hallmark of various cancer types, including melanoma. Chemotherapy may further increase tumour NFĸB activity, a phenomenon that, in turn, exacerbates drug resistance. This study aimed at preliminary screening of a panel of aromatic aldehydes, including vanillin, for cytotoxicity and suppression of tumour cell NFĸB activity. MATERIALS AND METHODS: The cytotoxic and NFĸB-inhibitory effects of 10 aromatic aldehydes, including vanillin, were investigated in cultured A375 human melanoma cells...
2016: Anticancer Research
Dong In Keum, Long-Quan Pi, Sungjoo Tommy Hwang, Won-Soo Lee
BACKGROUND: Chemotherapy-induced alopecia (CIA) is one of the most distressing side effects for patients undergoing chemotherapy. This study evaluated the protective effect of Korean Red Ginseng (KRG) on CIA in a well-established in vitro human hair follicle organ culture model as it occurs in vivo. METHODS: We examined whether KRG can prevent premature hair follicle dystrophy in a human hair follicle organ culture model during treatment with a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC)...
April 2016: Journal of Ginseng Research
Simona Bramante, Anniina Koski, Ilkka Liikanen, Lotta Vassilev, Minna Oksanen, Mikko Siurala, Raita Heiskanen, Tiina Hakonen, Timo Joensuu, Anna Kanerva, Sari Pesonen, Akseli Hemminki
Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules to boost virus triggered antitumoral immune responses. Cyclophosphamide (CP) is a chemotherapy drug that is associated with cytotoxicity and immunosuppression at higher doses, whereas immunostimulatory and anti-angiogenic properties are observed at low continuous dosage...
February 2016: Oncoimmunology
Jin Zhang, Hongxia Li
Ovarian cancer has a poor prognosis, primarily due to the heterogeneity in chemosensitivity among patients. In the present study, this heterogeneity was evaluated in ovarian epithelial cancer (OEC) using an in vitro adenosine triphosphate tumor chemosensitivity assay (ATP-TCA). Specimens were collected from 80 patients who underwent cytoreductive surgery. Viable ovarian cancer cells obtained from malignant tissues were tested for sensitivity to paclitaxel (PTX), carboplatin (CBP), topotecan (TPT), gemcitabine (GEM), docetaxel (TXT), etoposide, bleomycin and 4-hydroperoxycyclophosphamide using ATP-TCA...
May 2015: Oncology Letters
Sua Kim, Hyo-Jung Choi, Chor Ho Jo, Joon-Sung Park, Tae-Hwan Kwon, Gheun-Ho Kim
Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4-hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water-loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats...
September 1, 2015: American Journal of Physiology. Renal Physiology
Nadja Chevalier, Nicole Gross, Christian Widmann
Although current anti-cancer protocols are reasonably effective, treatment-associated long-term side effects, induced by lack of specificity of the anti-cancer procedures, remain a challenging problem in pediatric oncology. TAT-RasGAP317-326 is a RasGAP-derived cell-permeable peptide that acts as a sensitizer to various anti-cancer treatments in adult tumor cells. In the present study, we assessed the effect of TAT-RasGAP317-326 in several childhood cancer cell lines. The RasGAP-derived peptide-induced cell death was analyzed in several neuroblastoma, Ewing sarcoma and leukemia cell lines (as well as in normal lymphocytes)...
2015: PloS One
Yuki Tazawa, Ippei Usukubo, Kazuki Takada, Yoh Takekuma, Yoshihiro Shibayama, Mitsuru Sugawara
Combination chemotherapy is often used to treat cancer. Many studies have shown schedule-dependent effects between anticancer drugs. Our previous studies showed that K-562 cells pretreated with non-cytotoxic concentrations of 4-hydroperoxycyclophosphamide (4-HPC), which is a preactivated analog of cyclophosphamide (CY), enhanced the cytotoxicity of etoposide (VP-16). The appearance of cellular resistance to anticancer drugs is a major problem in cancer chemotherapy. P-Glycoprotein (P-gp) plays an important role in drug resistance, and VP-16 is a substrate for this efflux pump...
2014: Biological & Pharmaceutical Bulletin
Bibek Parajuli, Taxiarchis M Georgiadis, Melissa L Fishel, Thomas D Hurley
Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemoresistance, by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues, such as mafosfamide (MF), ifosfamide (IFM), and 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 could permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1-selective inhibitor, CB29, previously identified in a high-throughput screen...
March 21, 2014: Chembiochem: a European Journal of Chemical Biology
Eliska Potuckova, Hana Jansova, Miloslav Machacek, Anna Vavrova, Pavlina Haskova, Lucie Tichotova, Vera Richardson, Danuta S Kalinowski, Des R Richardson, Tomas Simunek
Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N'-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs...
2014: PloS One
Mingxi Liu, Barbara F Hales, Bernard Robaire
Treatment with chemotherapeutics agents may induce persistent DNA damage in male germ cells with the possibility of long-term consequences on fertility and progeny outcome. Telomeres, specialized structures at the physical ends of chromosomes, play an important role in the maintenance of genetic stability and in the response of somatic cells to anticancer drugs. Our objective was to test the hypothesis that exposure to bleomycin, etoposide, or cisplatin (the drugs used to treat testicular cancer) or cyclophosphamide (an anticancer agent and immunosuppressant) targets telomeres in the male germ line...
April 2014: Biology of Reproduction
N Pinto, E R Gamazon, N Antao, J Myers, A L Stark, A Konkashbaev, H K Im, S J Diskin, W B London, S M Ludeman, J M Maris, N J Cox, S L Cohn, M E Dolan
High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide (4HC; n = 422) and phosphoramide mustard (PM; n = 428). Genome-wide association studies were performed to identify single-nucleotide polymorphisms (SNPs) associated with sensitivity to 4HC and PM...
June 2014: Clinical Pharmacology and Therapeutics
Martha Rodriguez Sandoval, Kumudha Balakrishnan, Rajyalakshmi Luthra, Michael Keating, Varsha Gandhi
Mammalian ribonucleotide reductase (RR) is a heterodimer enzyme responsible for maintaining levels of deoxynucleotides needed for DNA replication. The M2 subunit of RR is known to increase in tandem with progression of cells into S phase, whereas the M1 subunit is expressed at steady-state. Since the expression level of the M2 subunit increases because the cells need deoxyribonucleoside triphosphates (dNTPs) for replication, it is logical to hypothesize that the same increase will be seen during DNA repair...
April 2014: Leukemia & Lymphoma
Quang-Dé Nguyen, Ioannis Lavdas, James Gubbins, Graham Smith, Robin Fortt, Laurence S Carroll, Martin A Graham, Eric O Aboagye
PURPOSE: Induction of apoptosis in tumors is considered a desired goal of anticancer therapy. We investigated whether the dynamic temporal and spatial evolution of apoptosis in response to cytotoxic and mechanism-based therapeutics could be detected noninvasively by the caspase-3 radiotracer [(18)F]ICMT-11 and positron emission tomography (PET). EXPERIMENTAL DESIGN: The effects of a single dose of the alkylating agent cyclophosphamide (CPA or 4-hydroperoxycyclophosphamide), or the mechanism-based small molecule SMAC mimetic birinapant on caspase-3 activation was assessed in vitro and by [(18)F]ICMT-11-PET in mice bearing 38C13 B-cell lymphoma, HCT116 colon carcinoma, or MDA-MB-231 breast adenocarcinoma tumors...
July 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Chunwei Huang, Barbara F Hales
Hypoxia plays a critical role in coordinating cell survival, differentiation and death in normal embryogenesis; during limb pattern formation, hypoxia affects two key processes, chondrogenesis and cell death. Hypoxia promotes chondrocyte differentiation and cartilage matrix synthesis and suppresses terminal differentiation. Depending on the context, hypoxia may induce cell cycle arrest, pro- or anti-apoptotic genes, or autophagy. The response to hypoxia is controlled by hypoxia inducible transcription factors, specifically Hif1a, Hif2a and Hif3a...
2012: PloS One
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