Novel CK2-Specific Pt(II) Compound Reverses Cisplatin-Induced Resistance by Inhibiting Cancer Cell Stemness and Suppressing DNA Damage Repair in Non-small Cell Lung Cancer Treatments

摘要

Cancer stem cells (CSCs) have a pivotal impact in drug resistance, tumor metastasis, and progression of various cancer entities, including in non-small cell lung cancer (NSCLC). A CK2 inhibitor HY1 was found to show potent CSC inhibitory effects in A549 cells. By taking advantage of inherent CK2 specificity and CSC inhibition of HY1, a Pt(II) agent (HY1-Pt) was developed by conjugation of HY1 with an active Pt(II) unit to reverse cisplatin-induced resistance in A549/cDDP cell treatment. In vitro biological studies indicated that HY1-Pt can target CK2, suppress DNA damage repair, reinforce cellular accumulation of platinum, and reverse resistance apart from effectively inhibiting CSCs through Wnt/beta-catenin signal pathway in A549/cDDP cells. Significantly, HY1-Pt presented an acceptable pharmacokinetic behavior and exhibited higher tumor growth inhibitory efficacy than cisplatin either in A549 or A549/cDDP xenograft models with low toxicity. Overall, HY1-Pt is a promising drug candidate for NSCLC treatment.