Enhancement of Bone Marrow CD41+ Megakaryocytes as well as Modulation of TNF-α, IL-12, and IL-5 by a Novel Small Molecule, UTL-5g, in Mice Treated with Cisplatin

¹ Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202

² 21^st Century Therapeutics, Inc., Detroit, Michigan 48202

³ Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan 48202

*Corresponding author

Dr. Jiajiu Shaw

21^st Century Therapeutics, Inc.

440 Burroughs St., Suite 447

Detroit, MI 48202

USA

Tel: (7348) 330-6052

E-mail: jiajiushaw@gmail.com

            liwei.gao@ncich.com.cn (Liwei Gao)

Abstract

UTL-5g is a novel small-molecule chemoprotective agent against cisplatin-induced host cytotoxicity. Recent studies showed that UTL-5g increased the blood platelet count, which was reduced in cisplatin-treated mice. In order to have a better understanding about the mechanism of action by which UTL-5g promotes platelet production, BDF1 mice were treated with or without UTL-5g after cisplatin treatment; several hematological analyses were conducted. The results showed that treatment of mice with UTL-5g alone by either i.p. injection or oral gavage markedly increased platelet counts. UTL-5g also restored bone marrow cell counts that were reduced by cisplatin treatment. Flow cytometric analysis showed that bone marrow CD41+ megakaryocytic cells were significantly increased in animals pretreated with UTL-5g before cisplatin. Measurement of secreted cytokines showed that pretreatment of UTL-5g lowered blood levels of both TNF-a and IL-12 (p70) elevated by cisplatin treatment. On the other hand, pretreatment of UTL-5g raised blood levels of IL-5 that were lowered by cisplatin treatment. The results also showed that 60 mg/kg is the optimal dose of UTL-5g by oral route for the protection of bone marrow cells, CD41+ megakaryocytes, and platelets. In conclusion, this study suggests that UTL-5g (by i.p. injection or oral gavage) enhances the production of platelets by either protecting or increasing bone marrow CD41+ megakaryocytic cells at least in part; UTL-5g also modulates TNF-a, IL-12 (p70), and IL-5. Taken together, these observed effects of UTL-5g on megakaryocytes and cytokines play important roles in the chemoprotective properties of UTL-5g.

Keywords: chemoprotective agent, cisplatin, platelets, CD41+ megakaryocytes, bone marrow cells

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