The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the u...The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.展开更多
Aim:Chemoresistance is the biggest obstacle in cancer treatment.Our previous study demonstrated that Shenmai injection(SMI),a Chinese herbal medicine,enhanced the antitumor effect of cisplatin via glucose metabolism r...Aim:Chemoresistance is the biggest obstacle in cancer treatment.Our previous study demonstrated that Shenmai injection(SMI),a Chinese herbal medicine,enhanced the antitumor effect of cisplatin via glucose metabolism reprogramming.This study aimed to further determine whether the SMI sensitizes the non-small cell lung cancer(NSCLC)cells to cisplatin through regulation mitochondrial dynamics.Methods:The Kaplan-Meier Plotter database was used to investigate the relationship between mRNA expression of mitofusin-2(Mfn2)and the survival analysis of NSCLC patients.The protein expression of Mfn2 in a lung adenocarcinoma tissue chip was detected by immunohistochemistry staining.The expression of Mfn2 and ATAD3A were compared between cisplatin-sensitive A549 and cisplatin-resistant A549/DDP cells.Additionally,A549/DDP cells were co-treated with cisplatin and SMI to detect mitochondrial morphology by fluorescent staining,apoptosis-related protein expression with Western blotting,and mitochondrial membrane potential(ΔΨm)with flow cytometry analysis.Results:The mean survival time of the Mfn2^(low) group was significantly lower than that of the Mfn2^(high) group by Kaplan-Meier Plotter database analysis,and the Mfn2 protein expression level was lower in cancer tissues than in adjacent tissues.The combination of SMI and cisplatin induced dynamic changes in A549/DDP cells,with increased mitochondrial fusion followed by upregulation of Mfn2 and downregulation of ATAD3A and reduced mitochondrial mass and ΔΨm.Moreover,SMI significantly enhanced cisplatin-induced A549/DDP apoptosis,upregulated Bax and the active subunit of caspase-3,and downregulated Bcl-2 expression,as shown via Hoechst staining and flow cytometry analysis.Conclusion:Our findings suggest SMI enhances cisplatin-induced apoptosis through regulation of Mfn2-dependent mitochondrial dynamics in cisplatin-resistant lung adenocarcinoma cells.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82172736,81972886,and 82172735]the State Key Laboratory of Systems Medicine for Cancer(No.ZZ94-2306)。
文摘The platinum-based chemotherapy is a routine strategy for the treatment of ovarian cancer,while it is prone to chemoresistance in clinical,which hinders the treatment.Therefore,it is urgently needed to elucidate the underlying mechanism of drug resistance and form the appropriate strategy.The sequencing results showed that cisplatin(DDP)resistant ovarian cancer overexpressed BTB and CNC homology 1(BACH1),and up-regulated the“don’t eat me”signal CD47.We identified that hemin,a BACH1 inhibitor,could effectively down-regulate BACH1 and simultaneously inhibit CD47.Moreover,hemin has a synergistic effect with DDP.We designed a pH-responsive nanoparticle(H/D@FA-CaP-NPs)in which folic acid(FA)ensured targeting of ovarian cancer cells,while hemin inhibited BACH1 as well as down-regulated CD47,achieving the promotion of apoptosis of tumor cells and inducing phagocytosis of tumors by macrophages.Moreover,hemin has a synergistic effect with DDP to promote apoptosis of tumor cells.Structurally,hemin and DDP was encapsulated within hydrophobic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine(DSPE)to form a tight core,and hydrophilic polyethylene glycol 2000(PEG2000)and calcium phosphate(CaP)formed the outside shell,and FA was modified on the surface of nanoparticles.In terms of function,(a)FA enhanced the active targeting of nanoparticles to tumors;(b)NPs targeted mitochondria to induce reactive oxygen species(ROS)production;(c)hemin encapsulated in nanoparticles could specifically target BACH1,thereby down regulating CD47;(d)hemin had a synergistic effect with DDP,thus augmenting the chemotherapy.Altogether,mitochondria-targeted nanoparticles H/D@FA-CaP-NPs promoted tumor apoptosis and mobilized phagocytosis to treat tumor,providing a novel scheme for clinical treatment of cisplatin-resistant ovarian carcinoma.
基金This work was financially supported by the National Natural Science Fund of China(Grants 82174254,81774184 and 81973735).
文摘Aim:Chemoresistance is the biggest obstacle in cancer treatment.Our previous study demonstrated that Shenmai injection(SMI),a Chinese herbal medicine,enhanced the antitumor effect of cisplatin via glucose metabolism reprogramming.This study aimed to further determine whether the SMI sensitizes the non-small cell lung cancer(NSCLC)cells to cisplatin through regulation mitochondrial dynamics.Methods:The Kaplan-Meier Plotter database was used to investigate the relationship between mRNA expression of mitofusin-2(Mfn2)and the survival analysis of NSCLC patients.The protein expression of Mfn2 in a lung adenocarcinoma tissue chip was detected by immunohistochemistry staining.The expression of Mfn2 and ATAD3A were compared between cisplatin-sensitive A549 and cisplatin-resistant A549/DDP cells.Additionally,A549/DDP cells were co-treated with cisplatin and SMI to detect mitochondrial morphology by fluorescent staining,apoptosis-related protein expression with Western blotting,and mitochondrial membrane potential(ΔΨm)with flow cytometry analysis.Results:The mean survival time of the Mfn2^(low) group was significantly lower than that of the Mfn2^(high) group by Kaplan-Meier Plotter database analysis,and the Mfn2 protein expression level was lower in cancer tissues than in adjacent tissues.The combination of SMI and cisplatin induced dynamic changes in A549/DDP cells,with increased mitochondrial fusion followed by upregulation of Mfn2 and downregulation of ATAD3A and reduced mitochondrial mass and ΔΨm.Moreover,SMI significantly enhanced cisplatin-induced A549/DDP apoptosis,upregulated Bax and the active subunit of caspase-3,and downregulated Bcl-2 expression,as shown via Hoechst staining and flow cytometry analysis.Conclusion:Our findings suggest SMI enhances cisplatin-induced apoptosis through regulation of Mfn2-dependent mitochondrial dynamics in cisplatin-resistant lung adenocarcinoma cells.
