| Background and purpose:Esophageal cancer has high incidence and mortality,and it ranks the 6th in mortality overall in global cancer statistics 2018.Surgery is the mainly treatment for early stage,while for advanced esophageal cancer,the combination of DDP and 5-FU is more common.These conventional treatments present many drawbacks.For example,radiotherapy and chemotherapy often lead to severe systemic adverse effects.The recurrence of some tumors after surgery cannot avoid.Photodynamic therapy(PDT)has quickly gained a place in the field of cancer prevention for its unique advantages and it has been approved by FDA for clinical treatment of multiple cancers.It is an important adjunctive therapy for esophageal cancer,and the photosensitizer is crucial for effective PDT.In our previous studies,we successfully prepared a new photosensitizer-PHE with high purity,good water solubility and high yield of singlet oxygen.Aerobic glycolysis is a common feature of energy metabolism in esophageal cancer cells,and studies suggest that cell autophagy triggered by PHE-PDT is involved in the regulation of glucose metabolism,which can play an important role in the resistance to PDT.The safety of PDT and its therapeutic effect have been clinically recognized,but recurrence after tumor regression is a common clinical phenomenon.The reason is unclear.It may be related to the autophagy stress and energy metabolism reprogramming of tumor cells after PDT treatment.Previous studies have showed that PHE-PDT has excellent inhibitory effect on esophageal cancer xenografts within two weeks,but tumor recurrence occurred in long-term observation,which is consistent with a large number of studies.In order to solve this problem,it is necessary to further explore the mechanism of tumor cell response after PHE-PDT.Higher aerobic glycolysis is a common feature of energy metabolism in esophageal cancer cells.Inhibition of glycolysis can significantly enhance the sensitivity of tumor cells to PDT,but the mechanism is still unknown.Studies suggest that PHE-PDT-triggered cellular autophagy is involved in the regulation of glucose metabolism and may play an important role in PDT-resistant.Based on the above research background and previous experimental results,this study aims to further analyze the interaction between autophagy and cell metabolism in the treatment of esophageal cancer with PHE-PDT.Firstly,the anti-tumor effect of PHE-PDT were investigated in vitro and in vivo.Then,the mechanism of tumor cell response to PHE-PDT was analyzed and the relationship between autophagy and metabolic reprogramming induced by PDT were analyzed after adding autophagy inhibitor CQ.Methods and results:1.Synthesis of PHE and the cytotoxic effect of PHE-PDT in Eca-109 cells.PHE was synthesed successful and it showed strong absorb at near infrared area,which implied that PHE has excellent penetration ability.Besides,it has a high singlet oxygen yield.The investigation about the cytotoxic effect of PHE-PDT in Eca-109 cells suggesting that it can cuase the reduction of cell survival.2.Energy metabolism reprogramming was triggered in Eca-109 cells by PHE-PDT.PHE-PDT caused mitochondria dysfunction,and lead to the reprogramming of energy metabolism in cells.The OXPHOS was decreased and glycolysis was increased in cells which were exposured to PHE-PDT.3.Autophagy inhibition enhanced the cytotoxic effect of PHE-PDT.Autophagy was observed in Eca-109 cells after PDT treatment,and inhibition of autophagy by CQ enhanced the killing effect of PHE-PDT.Cellular energy metabolism was evaluated and it was found that CQ combined with PHE-PDT declined the cell glycolysis.The possible mechanism is that autophagy induction via PDT facilitated glucose uptake by increasing the surface expression of Glut 1.Whereas inhibition of autophagy by CQ leads to a decrease in glycolysis and enhances the efficacy of PHE-PDT.4.In vivo therapeutic efficacy of PHE-PDT.Tumor-bearing mice were established,and the small animal living imaging system was used to explore the biodistribution of PHE in vivo and ex vivo.It was found that the optimal enrichment time of PHE in the tumor site after tail vein injection was 24 h.To evaluate the antitumor efficiency of PHE-PDT in combination with CQ,Eca-109 tumor-bearing mice were established and the mice were divided into control group,CQ group,PDT group or CQ+PDT group.After administrated different therapies,the antitumor effect was evaluated by the changes of tumor volume and tumor weight.There had no significant difference between control and CQ group,suggested CQ alone had no treatment effect.While the tumor volume and weight in PHE-PDT group was declined.The CQ plus PDT group had a further decrease in the tumor volume and weight compared with PDT group,implying that autophagy inhibition can enhance the antitumor effect of PHE-PDT in vivo.ConclusionIn this study,a novel sensitizer PHE was synthesized and it was successfully applied in PDT.We illustrated the interaction between PHE-PDT-induced autophagy and energy metabolism reprogramming.We also elucidated the possible regulation mechanism how autophagy regulate glycolysis in Eca-109 cells.This mechanism may provide potential targets for PDT clinical treatment of esophageal cancer. |
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