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      Carnosic acid enhances the anti-lung cancer effect of cisplatin by inhibiting myeloid-derived suppressor cells

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          Abstract

          Cisplatin and other platinum-based drugs are used frequently for treatment of lung cancer. However, their clinical performance are usually limited by drug resistance or toxic effects. Carnosic acid, a polyphenolic diterpene isolated from Rosemary ( Rosemarinus officinalis), has been reported to have several pharmacological and biological activities. In the present study, the combination effect of cisplatin plus carnosic acid on mouse LLC (Lewis lung cancer) xenografts and possible underlying mechanism of action were examined. LLC-bearing mice were treated with intraperitoneal injection with cisplatin, oral gavage with carnosic acid, or combination with cisplatin and carnosic acid, respectively. Combination of carnosic acid and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than drugs alone. Mechanistic study showed that carnosic acid treatment boosted the function of CD8 + T cells as evidenced by higher IFN-Γ secretion and higher expression of FasL, perforin as well as granzyme B. In the meantime, the proportion of MDSC (myeloid-derived suppressor cells) in tumor tissues were reduced by carnosic acid treatment and the mRNA levels of iNOS2, Arg-1, and MMP9, which are the functional markers for MDSC, were reduced. In conclusion, our study proved that the functional suppression of MDSC by carnosic acid promoted the lethality of CD8 + T cells, which contributed to the enhancement of anti-lung cancer effect of cisplatin.

          Author and article information

          Journal
          CJNM
          Chinese Journal of Natural Medicines
          Elsevier
          1875-5364
          20 December 2018
          : 16
          : 12
          : 907-915
          Affiliations
          [1] 1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China
          [2] 2Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
          Author notes
          *Corresponding authors: GUO Wen-Jie, E-mail: guowj@ 123456nju.edu.cn ; XU Qiang, molpharm@ 123456163.com

          ΔThese authors contributed equally to this work.

          These authors have no conflict of interest to declare.

          Article
          S1875-5364(18)30132-8
          10.1016/S1875-5364(18)30132-8
          30595215
          2e525813-171e-4da9-946c-fd8010361128
          Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
          History
          : 18 September 2018
          Funding
          Funded by: Natural Science Foundation of China
          Award ID: 81673437
          Award ID: 21472091
          Funded by: Postdoctoral Science Foundation of China and Jiangsu Province
          Award ID: 2018T110484
          Award ID: 2017M621721
          Award ID: 1701122B
          Funded by: Fundamental Research Funds for the Central Universities
          Award ID: 14380097
          This work was supported by Natural Science Foundation of China (Nos. 81673437 and 21472091), Postdoctoral Science Foundation of China and Jiangsu Province (Nos. 2018T110484, 2017M621721, and 1701122B), and Fundamental Research Funds for the Central Universities (No.14380097).

          Medicine,Pharmaceutical chemistry,Pharmacology & Pharmaceutical medicine,Complementary & Alternative medicine
          Lung cancer,MDSC,CD8+ T cell,Carnosic acid,Cisplatin

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