| Tumor is a serious threat to human life and health.Although researchers have developed various novel anti-tumor drugs and therapies in the past a few decades,there is still no radical cure for cancer now,people have a long way to go in cancer treatment.Despite Rosenberg first discovered the anti-tumor activity of cisplatin in 1960 s,and the research on platinum drugs has been deepening,the defects of traditional platinum drugs such as high toxic side effects and resistance have seriously limited their clinical use.Recent studies have shown that the mechanism of platinum resistance mainly includes(i)the loss of cell surface proteins,such as transporters,which lead to the decrease of intracellular platinum accumulation;(ii)biomolecules containing sulfhydryl groups such as glutathione(GSH)can inactivate cisplatin;(iii)DNA damage repair;(iv)reduced apoptosis and the functions of cancer stem cells(CSCs)which can drive tumorigenesis and growth.The purpose of this paper is to design and discover potential novel platinum complexes with targeted properties according to these mechanisms,which can effectively overcome cisplatin resistance to improve its anti-tumor activity.Tumor recurrence,metastasis and acquired resistance have severely limited the effect of clinical treatments for epithelial ovarian cancer(EOC).A platinum(II)complex Ⅰ owning CK2 specificity reported in our recent research was herein applied to treat EOCs.Our research indicated that complex Ⅰ exhibited potent cytotoxicity against both cisplatin-sensitive and cisplatin-resistant epithelial ovarian cancer cells in vitro,blocked cell cycle and induced cell apoptosis.Meanwhile,complex Ⅰ showed excellent anti-tumor activity on A2780 and A2780/CDDP mouse xenograft tumor models,with a tumor inhibition rate of more than 95% at a dose of 40 mg/kg.In the study of mechanism,the down-regulation of CK2α expression in A2780/CDDP cells led to decreased cancer cell stemness,invasion and migration.Therefore,complex Ⅰ was found to function as a CK2 inhibitor in A2780/CDDP cells,down-regulated cancer cell stemness and tumor metastasis by regulation of Wnt/β-catenin signaling pathway.Our study indicates that complex Ⅰ has potential benefit in curing epithelial ovarian cancer no matter it is sensitive or resistant to cisplatin,providing a promising way to overcome platinum drug resistance.Then focused on the drug-resistant mechanism of DNA damage repair,we herein reported the platinum(II)complexes owning PARP specificity,derived from a known PARP inhibitor olaparib in axial position,to treat with ovarian cancer.Among them,complex Ⅱ-1could significantly inhibit the activity of PARP1,showing the potent cytotoxicity against both cisplatin-sensitive and cisplatin-resistant epithelial ovarian cancer cells in vitro,while dose-dependently inhibited tumor growth in SKOV3 xenograft models,with a tumor inhibition rate of 74.10% at a dose of 40 mg/kg.Futher assays indicated that complex Ⅱ as a platinum(II)complex could induce DNA damage,suppress DNA damage repair as a PARP inhibitor by regulation of HR mechanism,achieving higher DNA damage level to overcome cisplatin resistance and induce cell apoptosis.Therefore,complex Ⅱ as a targeting platinum(II)complex can provide a reference for the design of novel platinum-based drugs.Finally,based on the serious side-effects and CSCs caused resistance of platinum(II)drugs,we designed and synthesized a series of platinum(IV)complexes by introducing known CSCs inhibitor BBI608 derivatives into the axial position of platinum(IV)intermediates derived from cisplatin via ester bonding.Among them,complex Ⅲ-6 exerted much potent cytotoxicity against both cisplatin sensitive and resistant non-small cell lung cancer cell lines A549 and A549/CDDP,superior to cisplatin and BBI608.As expected,complex Ⅲ-6 had the ability to suppress cancer cell stemness superior to BBI608,resulting in overcoming cisplatin resistance.Biological studies indicated that complex Ⅲ-6 could trigger DNA damage and ROS generation to induce cell apoptosis.In vivo tests on A549/CDDP xenograft models confirmed that complex Ⅲ-6 showed high anti-tumor efficacy and could effectively overcome cisplatin resistance with low toxicity.In summary,our study provides a novel and efficient approach to promote the anti-tumor activity of platinum-based drugs,overcome cisplatin resistance via inhibiting cell stemness and DNA damage repair in cancer cells. |
