Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle

FEBS Letters

Puigjaner, Joaquim²  Boros, Laszlo G³  Raı̈s, Badr²  Comin, Begoña²  Ennamany, Rachid⁴  Saboureau, Dominique⁴  Cascante, Marta²  Brandes, James L¹  Paul Lee, Wai-Nang³  Creppy, Edmond⁴ 

[1] The Ohio State University College of Medicine, Department of Surgery, 400 West 12th Ave. N217, Wiseman Hall, Columbus, OH 43210, USA;Department of Biochemistry and Molecular Biology, Institut d'Investigacions Biomèdiques August Pi i Sunyer. University of Barcelona, C/Marti i Franquès 1, 08028 Barcelona, Spain;Research and Education Institute, Harbor-UCLA Medical center, RB1, 1124 West Carson Street, Torrance, CA 90502, USA;Laboratory of Toxicology and Applied Hygiene, Faculty of Pharmaceutical Sciences, University of Bordeaux II. 146, Rue léo-Saignat, 33076 Bordeaux, France

关键词: Cell cycle regulation;    Glucose metabolism;    Oxythiamine;    Dehydroepiandrosterone;    TK;    transketolase;    OT;    oxythiamine;    PC;    pentose cycle;    DHEA;    dehydroepiandrosterone;    PI;    propidium iodide;    DMSO;    dimethylsulfoxide;    i.p.;    intraperitoneal;    FSC;    forward scatter;    SSC;    side scatter;    H;    hematoxilin;    E;    eosin;   

DOI  :  10.1016/S0014-5793(99)00924-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Transketolase (TK) reactions play a crucial role in tumor cell nucleic acid ribose synthesis utilizing glucose carbons, yet, current cancer treatments do not target this central pathway. Experimentally, a dramatic decrease in tumor cell proliferation after the administration of the TK inhibitor oxythiamine (OT) was observed in several in vitro and in vivo tumor models. Here, we demonstrate that pentose cycle (PC) inhibitors, OT and dehydroepiandrosterone (DHEA), efficiently regulate the cell cycle and tumor proliferation processes. Increasing doses of OT or DHEA were administered by daily intraperitoneal injections to Ehrlich's ascites tumor hosting mice for 4 days. The tumor cell number and their cycle phase distribution profile were determined by DNA flow histograms. Tumors showed a dose dependent increase in their G₀-G₁ cell populations after both OT and DHEA treatment and a simultaneous decrease in cells advancing to the S and G₂-M cell cycle phases. This effect of PC inhibitors was significant, OT was more effective than DHEA, both drugs acted synergistically in combination and no signs of direct cell or host toxicity were observed. Direct inhibition of PC reactions causes a G₁ cell cycle arrest similar to that of 2-deoxyglucose treatment. However, no interference with cell energy production and cell toxicity is observed. PC inhibitors, specifically ones targeting TK, introduce a new target site for the development of future cancer therapies to inhibit glucose utilizing pathways selectively for nucleic acid production.

【 授权许可】

Unknown