Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer

Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize with enzalutamide,a second-generation AR inhibitor,in TNBC.By using a strategy for screening drug combinations based on the Sensitivity Index(SI),we found that MK-8776,a selective checkpoint kinase1(CHK1)inhibitor,showed favorable synergism with enzalutamide in AR-positive TNBC.The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776,respectively.Furthermore,a nanoparticle-based on hyaluronic acid(HA)-modified hollow-manganese dioxide(HMnO_(2)),named HMnE&M@H,was established to encapsulate and deliver enzalutamide and MK-8776.This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness.HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier.Collectively,our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H,providing a potential therapeutic approach for the treatment of TNBC.

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell(CSC)populations.In this study,we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line.Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations.However,the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis.Collectively,the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.