The treatment of non-small cell lung cancer(NSCLC)remains a challenge due to tumor evolution during anti-angiogenesis therapies,in which the mechanism of vascular mimicry(VM)is believed to result in ineffective treatm...The treatment of non-small cell lung cancer(NSCLC)remains a challenge due to tumor evolution during anti-angiogenesis therapies,in which the mechanism of vascular mimicry(VM)is believed to result in ineffective treatment[1].To conquer this challenge,substantial effort has recently been devoted to seeking out natural compounds on account of their multitarget actions.As a traditional herbal medicine,platycodin D(PD)is the major bioactive monomer derived from Platycodon grandiflorum(P.grandiflorum)and is used as an expectorant for pulmonary disease in Asia[2].展开更多
Objective Aberrant activating mutations in cyclin-dependent kinases 4 and 6(CDK4/6)are common in various cancers,including gastroesophageal malignancies.Although CDK4/6 inhibitors,such as abemaciclib and palbociclib,h...Objective Aberrant activating mutations in cyclin-dependent kinases 4 and 6(CDK4/6)are common in various cancers,including gastroesophageal malignancies.Although CDK4/6 inhibitors,such as abemaciclib and palbociclib,have been approved for breast cancer treatment,their effectiveness as a monotherapy remains limited for gastroesophageal tumors.The present study explored the underlying mechanism of abemaciclib resistance.Methods Abemaciclib-resistant gastric cancer cell lines were generated,and the phospho-eukaryotic translation initiation factor 4E(p-eIF4E)and eIF4E expression was compared between resistant and parental cell lines.In order to analyze the role of eIF4E in cell resistance,siRNA knockdown was employed.The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model.Results The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment.Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition,especially those that were resistant to abemaciclib.Ribavirin,which is an approved anti-viral drug,significantly improved the efficacy of abemaciclib,both in vitro and in vivo,by inhibiting eIF4E.Importantly,ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity.Conclusion These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer,proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.展开更多
基金funded by the National Natural Science Foundation of China(Grant Nos.:82004081 and 52073145)the National Natural Science Foundation of Nanjing University of Chinese Medicine,China(Grant No.:NZY82004081).
文摘The treatment of non-small cell lung cancer(NSCLC)remains a challenge due to tumor evolution during anti-angiogenesis therapies,in which the mechanism of vascular mimicry(VM)is believed to result in ineffective treatment[1].To conquer this challenge,substantial effort has recently been devoted to seeking out natural compounds on account of their multitarget actions.As a traditional herbal medicine,platycodin D(PD)is the major bioactive monomer derived from Platycodon grandiflorum(P.grandiflorum)and is used as an expectorant for pulmonary disease in Asia[2].
基金supported by the Nature Science Foundation of Hubei Province(No.2017CFB606).
文摘Objective Aberrant activating mutations in cyclin-dependent kinases 4 and 6(CDK4/6)are common in various cancers,including gastroesophageal malignancies.Although CDK4/6 inhibitors,such as abemaciclib and palbociclib,have been approved for breast cancer treatment,their effectiveness as a monotherapy remains limited for gastroesophageal tumors.The present study explored the underlying mechanism of abemaciclib resistance.Methods Abemaciclib-resistant gastric cancer cell lines were generated,and the phospho-eukaryotic translation initiation factor 4E(p-eIF4E)and eIF4E expression was compared between resistant and parental cell lines.In order to analyze the role of eIF4E in cell resistance,siRNA knockdown was employed.The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model.Results The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment.Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition,especially those that were resistant to abemaciclib.Ribavirin,which is an approved anti-viral drug,significantly improved the efficacy of abemaciclib,both in vitro and in vivo,by inhibiting eIF4E.Importantly,ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity.Conclusion These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer,proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.
