Two Natural Compounds Suppress Cancer Cell Invasion Through Downregulating The Expression Of CXCR4 Chemokine Receptor And Actinomycin D Inhibits NSCLC Tumor Growth By Targeting Warburg Effect

?. Two natural compounds Suppresses Cancer Cell Invasion through Inhibiting the Expression of CXCR4 Chemokine ReceptorCancer metastasis is the main cause of death (90%), and only recently we have gained some insight into the mechanisms by which metastatic cells arise from primary tumors and target to specific organs. Cysteine X Cysteine (CXC) chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is overexpressed in various tumors and mediates homing of tumor cells to distant sites expressing its cognate ligand CXCL12. Currently, CXCR4 antagonists, such as AMD3100 and ALX40-4C have entered clinical use in cancer treatment. However, due to several clinical problems including off-target effects of current antagonists, identification of other CXCR4 inhibitors has great potential to abrogate tumor metastasis.In this study, we demonstrated that xanthohumol (XN), a prenylflavonoid derived from the female flowers of the hops plant (Humulus lupulus. L), and acetyl-11-keto-?-boswellic acid (AKBA), a component in gum resin of therapeutic plant Boswellia serrata, suppressed CXCR4 expression in various cancer cell types in a concentration- and time-dependent manner. Both proteasome and lysosomal inhibitors had no effect to prevent the downregulation of CXCR4, suggesting that their inhibitory effect was not due to proteolytic degradation but occurred at the transcriptional level. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed that they could block endogenous activation of nuclear factor kappa B, a key transcription factor regulating the expression of CXCR4 in cancer cells. Consistent with the above molecular basis, XN and AKBA remarkably abolished CXCL12-induced cancer cell invasion. Interestingly, although co-exist in hops, XN was the only compound that exhibited the inhibitory effect on the expression of CXCR4 compared with other analogues, isoxanthohumol and 8-prenylnaringenin.Together, our results suggeste that XN and AKBA, as novel inhibitors of CXCR4, could be a promising cancer therapeutic agent.?. A FDA-approved drug-actinomycin D inhibit the growth of non-small cell lung cancer by targeting the warburg effectCurrently, Lung cancer is the leading cause of cancer mortality worldwide, and most of them (85%) are classified as non-small cell lung cancer. Warburg effect (aerobic glycolysis) as major abnormal metabolism existing in the majority of solid tumors, including non-small cell lung cancer, has become a new target for cancer therapy. Among tens of regulators in Warburg effect, HIF1 is the most important one in this process. However, due to several clinical problems of current glycolytic inhibitors, it is urgently needed to identify novel, effective and safe inhibitors targeting Warburg effect for non-small cell lung cancer treatment. FDA-approved drugs possess well-established safety and pharmacokinetic profiles, as well as manufacturing and distribution networks. Therefore, by screening these drugs, we can greatly shorten the period of novel drug discovery. The goal of this study is to identify old FDA-approved drugs with new functions targeting tumor abnormal metabolism.We first screened 1280 FDA-approved small molecules by cell viability assay and excluded those drugs with cancer cell inhibitory rates lower than 40% (at dose of 50 ?M). One hundred and eighty eight drugs were left for lactate release analysis and 4 candidates were screened out. The effects of these 4 drugs on glucose uptake, extracellular acidification rate, glycolytic capacity of cells, ATP production and cellular oxygen consumption rate were further evaluated. Actinomycin D effectively suppressed tumor glycolytic phynotypes in vitro in a concentration-dependent manner. Additionally, at a dose of 60 ?g/kg i.v. twice a week for 30 days, actinomycin D remarkably inhibited tumor growth and glucose uptake of the tumor tissue, indicating actinomycin D targeting warburg effect. Thus, we chose actinomycin D as drug candidate and for detailed mechanism study.Actinomycin D was one of the most important peptide antibiotics isolated from soil bacteria of the genus Streptomyces, and was originally shown to have the ability to inhibit transcriptional activity. In this study, we found that actinomycin D, with or without cobalt chloride, could inhibit the expression of the key kinases downstream of HIF1 in glycolytic pathway with a concentration- and time-dependent manner. The mechanism of inhibition did not occur at HIF1 protein levels, but was due to the downregulation of HIF1 transcription activity. Through nuclear/cytoplast separation, we confirmed that actinomycin D blocked HIF1 a translocation into the nucleus in the presence of cobalt chloride. Further co-immunoprecipitation study showed actinomycin D significantly attenuated the interaction of HIF1 a and PKM2, which hindered the formation of HIF1 transcriptional complex, resulting in the blocking of the expression of key kinases in glycolytic pathway.In this study, we found that actinomycin D inhibited tumor glycolysis by interfering with HIFla pathway. Our results provides valuable theoretical guidance for clinical applications of actinomycin D.