OPCs Abate The Prometastatic Potential Of Irradiation In Lung Cancer

Objective:To date,radiation therapy(RT)-induced tumor metastasis is widely recognized as a prominent problem which leads to an immense mortality in patients with lung cancer.As the active anti-oxidative components obtained from fruits and beverages such as grapes and red wine,oligomeric proanthocyanidins(OPCs)have been confirmed to exhibit a promising anti-tumor property in previous studies.However,few has put their focus on the impacts of OPCs on tumor post-irradiation progression,particularly on metastasis.This study investigated the advantages of OPCs in RT-elicited lung cancer metastasis and explored the potential mechanisms.Methods:A549-bearing nude mice were administered with OPCs and/or RT treatment.Tumor volume was recorded during the treatment schedule.The expression of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)was detected by gelatin zymography and immunohistochemical analysis.Non-small cell lung cancer cell lines(A549、H1975、95C、95D)and small cell lung cancer cell line(H446)were developed to investigate the outcomes and toxicities of OPC and RT in vitro.Cell viability was determined by cell counting kit-8(CCK-8)assay.The radiosensitization effect of OPC was evaluated by clonogenic survival.Cell cycle progression was determined by flow cytometric analysis.Radiation-induced DNA double strand break(DSB)was detected by the staining of y-H2AX.The migration and invasion ability of lung cancer cells was measured by wound healing and transwell assays.Activity of MMPs was determined by gelatin zymography.Alternation of epithelial-mesenchymal transition(EMT)regulators was detected by Western blot analysis.Results:The results indicated that OPCs markedly enhanced the radioresponses such as decreasing tumor’s volume and weight,with a significant reduction of MMP-2/-9 in A549-bearing xenografts(P<0.05).In vitro findings also showed that OPCs presented a striking irradiation synergy.OPCs notably inhibited the migration and invasion in A549 and H446 cell lines(P<0.05)while no obvious inhibition in tumor growth was observed.These effects might be due to the induction of y-H2AX foci and the remission of EMT elicited by RT(P<0.05),but not the blockage of cell cycle.Conclusion:OPCs alleviate irradiation-induced tumor prometastatic potential,which highlights a novel profile of OPCs as potent agents for preventing post-radiation recurrence and metastasis in patients with lung cancer.The improved radioresponse arises from preventing tumor EMT and a reduction in MMPs.