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.