Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

Xixi Lin,Eitan Anenberg,Fang Wang,Jianping Zhu,Xinwei Dong,Yanyou Li,Jian Shen,Yongliang Jia,Xiaoping Chen,Yicheng Xie,Yachao Jin,Jiancang Zhou,Qiangmin Xie

doi:10.3389/fphar.2019.00982

Abstract

Background: Platinum-based drugs prevail as the main treatment of lung cancer; this is caused by their relative effectiveness despite known side effects, such as neurotoxicity. The risk reward of the treatment and side effects is confronted when dosage is considered and when resistance to treatment develops. Development of new compounds that improve effectiveness and safety profiles addresses this ongoing need in clinical practice. Objectives: The novel water-soluble platinum complex, diplatin, was synthesized, and its antitumor potency and toxicology profile were evaluated in murine xenograft tumor models and in lung cancer cell lines. Methods: The effects of diplatin, cisplatin (DDP), and carboplatin (CBP) on the viability of nine lung tumor cell lines and one normal human lung epithelial cell line were evaluated using the MTT assay. Therapeutic index was calculated as LD50/ED50 to identify and compare the ideal therapeutic windows of the above compounds. Diplatin’s antitumor effects were assessed in lung xenograft tumors of nude mice; molecular mechanisms of therapeutic effects were identified. 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 inhibited the growth of DDP-resistant lung tumor cells. Diplatin’s mode of action was characterized to be through 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 antitumor effects in mice with both greater potency and safety compared with DDP and CBP. These observations indicate that diplatin is promising as a potential treatment in future clinical applications.

Highlights

Immense efforts are being made to prevent and treat lung cancer while cancer morbidity and mortality are ongoing (Hirsch et al, 2017)
Therapeutic index (TI) is the ratio of median lethal dose (LD50) to median effective dose (ED50) for a drug; a large TI indicates a wider window of safety for an effective treatment (Snider et al, 2016)
We found the TI of diplatin, DDP, and CBP to be 9.53, 2.17, and 2.52, respectively, giving diplatin the largest window of safety

Summary

Introduction

Immense efforts are being made to prevent and treat lung cancer while cancer morbidity and mortality are ongoing (Hirsch et al, 2017). Current treatment approaches are based on the use of platinumbased drugs, such as cisplatin (DDP) and carboplatin (CBP), these compounds lesion the DNA of cancer cells effectively (Muggia et al, 2014; Carenco et al, 2015), but their practical clinical application is limited by severe toxicity. DDP can induce nephrotoxicity, neurotoxicity, and ototoxicity, whereas CBP causes myelosuppression, hepatotoxicity, and gastrointestinal side effects (Olaussen et al, 2006). Resistance to these drugs can be acquired (Galanski and Keppler, 2007), and toxicity can limit the doses that can be administered. Platinum-based drugs prevail as the main treatment of lung cancer; this is caused by their relative effectiveness despite known side effects, such as neurotoxicity. Development of new compounds that improve effectiveness and safety profiles addresses this ongoing need in clinical practice

Objectives

Methods

Results