The Discovery Of Anti-tumor Effect Of The Novel Photosensitizer And Its Molecular Mechanism

The advantages of Photodynamic therapy(PDT)and the anti-tumor effect of the photosensitizer are characterized by directional destruction of tumor and its compatibility with other treatments.Although a considerable number of photosensitizers were already used in clinical application,their relatively poor dark toxicity against tumor cells raised concerns.Therefore,looking for the novel photosensitizer with low toxicity and high effectiveness has become one of the major objectives of anti-tumor drug studies.Carbonyl-phenalene-2,3-dicarbonitrile derivatives have good spectroscopic properties but contain high toxicity and side-effects,which prohibit them from current clinical applications.Research and development of novel carbonyl-phenalene derivatives are of great significance for the development of cancer treatment.In the previous studies,a series of carbonyl-phenalene derivatives with good level of singlet oxygen caught the attention of the cancer therapeutic field.Therefore,the purpose of this research is to discover the novel photosensitizer with high activity and low toxicity via the development of a screening model of anti-tumor photosensitizer,and thus sets the foundation for further studies.In this research,3B,a hydrolyzed derivative of carbonyl-phenalene-2,3-dicarbonitrile,was indicated to have a significant anti-tumor effect and low toxicity.Its anti-tumor effect and mechanisms were elucidated through its anti-tumor activity in different cancer cell lines by MTT assay.Among the results,MCF7 human breast cell(IC50=19.8±1.2?M)were the most positive and contained relatively low toxicity in normal human cell line(IC50>50?M).The results also demonstrated that 3B was primarily accumulated in mitochondria,induced death of apoptotic cells by Hoechst assay and flow cytometry.The apoptosis mechanism of 3B was confirmed by the protein and mRNA level of mitochondrial pathway.The photosensitizer produces ROS in order to destroy cancer cells.This study was intended to determine that 3B,a novel photosensitizer,increased the level of ROS.and inhibited glycolysis and inflammation in order to affect the Warburg effect in breast cancer cells.Warburg effect plays a very important role in tumor metabolism and it can be used to differentiate tumor cells from normal cells.Warburg effect is related to miRNA,which is a novel small non-coding RNA that is able to involve in biological functions through the regulation of target genes.Therefore,the development of the combination of metabolism and miRNA is a new research direction for tumor therapy.The present study indicated that 3B featured a significant inhibitory effect on the expression of miR-155-5p and SOCS1 might serve as a target gene of JAK/STAT pathway.On the other hand,it affected tumor cell proliferation through the anti-glycolytic effect and inflammation pathway via miR-155-5p.It proved the correlation between Warburg effect and miRNA.In vivo study,3B made a significant inhibition of tumor growth and showed drug toxicity hardly.3B inhibited the volume of tumors(Control group:425±48 mm3;PDT group:179 ±34 mm3)and the weight of tumors(Control group:584±88mg;PDT group:335±77mg).These data supported that 3B might develop as a potential therapeutic drug for the treatment of cancer not only in vitro but also in vivo.The structure of compounds could help explore its potential anti-tumor effect.Molecular docking system indicated that 3B could theoretically be combined with TGF-?R1 in order to decrease the combination of TGF-?R and TGF-? Furthermore,it could inhibit the level of lnc-ATB,which was made active by TGF-?.Q-PCR assay complied with this result and lnc-ATB would reserve for further studies.Here,lnc-ATB was significantly up-regulated in GC tissues compared to lnc-ATB expression irn ANTs and it could become potential molecular markers in clinical diagnosis of gastric cancer.Low levels of lnc-ATB inhibited GC cell proliferation and cell cycle arrest in vitro.It was found that lnc-ATB was directly bound with miR-141-3p and it affected the target gene TGF-?2.It was also demonstrated that lnc-ATB fulfilled its oncogenic roles in a ceRNA-mediated manner.Moreover,the positive feedback loop of lnc-ATB/miR-141-3p/TGF-?2 might be a potential therapeutic target for the treatment of GC.In conclusion,this research applied the novel carbonyl-phenalene derivative to the study of photodynamic therapy and anti-tumor effect,more specifically in the molecular mechanism of the novel carbonyl-phenalene derivative 3B in vitro and in vivo.The results showed that 3B inhibited cancer cells proliferation and had its potential target.Ultimately,the research has been an experimental basis for the further research of anti-tumor drugs.