The Anti-metastatic Effect Of MTOR And PRAK Inhibitors

Objective Metastasis to distant organs accounts for the majority of cancer-related death.No drug is currently available for the prevention of tumor metastasis.As a new therapeutic target,m TOR has drawn much attention in cancer treatment in recent years.But its potential in the control of metastasis remains to be fully explored.PRAK represents another key molecule in metastasis recently defined by our laboratory.The present study is aimed to interrogate the potential of m TOR inhibitor rapamycin and PRAK inhibitor XZP-0353 in metastasis intervention.Method Liver and lung metastasis models were established through intrasplenic and intravenous injection of B16-F10 cells,respectively.Different compounds were tested for their inhibitory effect on the development of metastatic lesions,followed by pathological examination.MTT,migration and transwell assays were performed to evaluate the proliferation,migration and invasion of tumor cells in the presence or absence of therapeutic agents.In addition,Western blot was used to determine the activation and expression levels of key proteins downstream of the PRAK pathway.Results In the liver metastasis model,m TOR inhibitor rapamycin can significantly led to a reduction in the number of metastatic lesions.Consistent with this,cell experiments show that rapamycin has obvious inhibitory effect on tumor cell migration and invasion,and the inhibitory effect is dose-dependent.In the lung metastasis model,intraperitoneal injection of PRAK inhibitor XZP-0353 led to a reduction in the number of metastatic lesions,recapitulating the loss of metastatic capacity of PRAK-deficient tumor cells.While similar results were obtained with intramuscular injection of XZP-0353,the anti-metastatic effect was almost completely absent following intravenous or oral administration.Comparable levels of plasma concentration of the drug were achieved when XZP-0353 was administrated through different approaches,indicating the differential effect was not due to variations in drug absorption.In addition,no difference was observed for PRAK-related inhibitory activities present in the mouse serum.Conclusion Rapamycin inhibits liver metastasis of melanoma,which may be attributable to the suppressed capacity of migration and invasion of tumor cells.With respect to the PRAK inhibitor XZP-0353,the approaches of drug administration has a profound impact on its therapeutic potential.While the reason remains to be defined for such differences,drug absorption is apparently not involved.These results may have important implications for further development of related therapeutic agents.