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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00982

Diplatin, a novel low toxicity and less resistance anti-lung cancer platinum complex activates cell death in tumors via a ROS/JNK/p53 dependent pathway

 Xixi Lin1, 2, Yongliang Jia3, 4, Xinwei Dong3, 4, Jian Shen3, 4, Yachao Jin4, Yanyou Li5, Fang Wang6,  Eitan Anenberg1,  Jiancang ZHOU7, Jianping Zhu7, Xiaoping Chen5,  Qiangmin Xie1, 3 and  Yicheng Xie1*
  • 1Children's Hospital, School of Medicine, ZheJiang University, China
  • 2Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, China
  • 3School of Medicine, Zhejiang University, China
  • 4Independent researcher, China
  • 5Beijing Shuobai Pharmaceutical Co., LTD, China
  • 6JOINN Laboratories, China
  • 7Sir Run Run Shaw Hospital, China

BACKGROUND: Platinum based drugs prevail in the treatment of lung cancer due to their relative effectiveness despite known side effects such as neurotoxicity. There is a need for testing of new compounds for improved effectiveness and safety profiles in order to develop new treatments for clinical practice.
OBJECTIVES: A novel water soluble platinum complex-diplatin was synthesized, its anti-tumor potency and toxicology profile were evaluated in both murine models of xenograft tumors and lung cancer cell lines.
METHODS: The effects of diplatin, cisplatin (DDP) and carboplatin (CBP) on the viability of 9 lung tumor cell lines and one normal human lung epithelial cell line were evaluated using MTT assay. Therapeutic index (TI) was calculated as LD50/ED50 to identify and compare the ideal therapeutic window of the above compounds. Diplatin anti-tumor effects were assessed in lung xenograft tumors of nude mice; molecular mechanisms of therapeutic effects were also elucidated.
RESULTS: Diplatin had desirable IC50 compared to CBP in a variety of cultured tumor cells notably lung tumor cells. In the mouse xenograft lung tumor diplatin led to a substantially improved therapeutic index when compared to the effects of DDP and CBP. Importantly, diplatin could inhibit the growth of DDP resistant lung tumor cells. Diplatin’s mode of action was cell cycle arrest in the G2/M phase and induction of lung tumor apoptosis via ROS/JNK/p53-mediated pathways.
CONCLUSION: Diplatin was observed to have anti-tumor effects in mice with both greater potency and safety. These observations indicate that diplatin is a promising candidate compound for clinical applications.

Keywords: lung cancer, Platinum complex, Water solubility, ROS/p53 pathway, cisplatin resistance

Received: 06 May 2019; Accepted: 31 Jul 2019.

Copyright: © 2019 Lin, Jia, Dong, Shen, Jin, Li, Wang, Anenberg, ZHOU, Zhu, Chen, Xie and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Yicheng Xie, Children's Hospital, School of Medicine, ZheJiang University, Hangzhou, Zhejiang Province, China, ycxie@zju.edu.cn