Study On The Antitumor Effect And The Mechanism Of Platinum(Ⅳ) Prodrug Based On TDO Inhibitor To Reverse Cisplatin Resistance

The treatments of malignant tumors have always been a worldwide problem,while the death rate of lung cancer is the highest among them.Poor prognosis and drug resistance are the main limitations of clinical treatments of lung cancer.Cisplatin is a first-line chemotherapy drug in the clinical treatment of lung cancer,but the acquired resistance induced by cisplatin limits its effect.Therefore,the development of new platinum-based drugs to overcome cisplatin resistance is crucial to improve the clinical treatment of lung cancer.Currently,the kinetic inertia of the platinum（Ⅳ）compound and its low spin d6 configuration improve the pharmacological action of platina-based anticancer drugs,making them the most promising candidate drugs.The chemotherapy method,while effective,is still limited.Therefore,immunotherapy is gradually coming into people’s vision,which can significantly improve the survival rate of patients and improve their quality of life.Tryptophan-2,3-dioxygenase（TDO）is a rate-limiting enzyme of important metabolic pathway of tryptophan and has been overexpressed in a variety of cancers,making TDO as a potential target.This study focused on the antitumor effect of DN604-TDOi,a novel platinum（Ⅳ）compound,and the mechanism of the reversal of cisplatin resistance.In this study,a series of assays confirmed the high toxicity of DN604-TDOi in cisplatin-sensitive human non-small cell lung cancer cell line A549 and cisplatin-resistant cell line A549/c DDP.DN604-TDOi could induce the expressions of caspase-3 and Bax proteins,inhibit the expression of Bcl-2 protein,induce the decrease of mitochondrial membrane potential,increase the level of reactive oxygen species,and force cell cycle to arrest in S phase and G2/M phase to promote the apoptosis of cancer cells.Meanwhile,DN604-TDOi could also regulate the immune response by inhibiting the expression of TDO2 protein and inducing the proliferation of CD⁴⁺T cells and CD⁸⁺T cells.More important,the increased platinum content in cells,decreased expression of DNA repair protein PARP1,translesion synthesis DNA polymerases REV1,POL kappa,POL zeta and cellular content of canine urine could make A549/c DDP cells more sensitive to DN604-TDOi.In conclusion,DN604-TDOi,as a new platinum（Ⅳ）compound,has the combined effects of chemotherapy and immunotherapy.