title: Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine.
abstract: OBJECTIVE
  Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid, a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated.
  
  
  METHODS
  The effect of ursolic acid on proliferation of CRC cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and protein expression by Western blot. The effect of ursolic acid on the growth and chemosensitization was also examined in orthotopically implanted CRC in nude mice.
  
  
  RESULTS
  We found that ursolic acid inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, and survivin), proliferative (cyclin D1), and metastatic (MMP-9, VEGF, and ICAM-1) proteins. When examined in an orthotopic nude mouse model, ursolic acid significantly inhibited tumor volume, ascites formation, and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that ursolic acid downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, ursolic acid suppressed EGF receptor (EGFR) and induced p53 and p21 expression. We also observed bioavailability of ursolic acid in the serum and tissue of animals.
  
  
  CONCLUSIONS
  Overall, our results show that ursolic acid can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis.
authors: Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Sahdeo
authors: S
authors: Prasad
authors: Vivek R
authors: VR
authors: Yadav
authors: Bokyung
authors: B
authors: Sung
authors: Simone
authors: S
authors: Reuter
authors: Ramaswamy
authors: R
authors: Kannappan
authors: Amit
authors: A
authors: Deorukhkar
authors: Parmeswaran
authors: P
authors: Diagaradjane
authors: Caimiao
authors: C
authors: Wei
authors: Veerabhadran
authors: V
authors: Baladandayuthapani
authors: Sunil
authors: S
authors: Krishnan
authors: Sushovan
authors: S
authors: Guha
authors: Bharat B
authors: BB
authors: Aggarwal
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000069287:Capecitabine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism; D000097245:Ursolic Acid
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D003841:Deoxycytidine; D066246:ErbB Receptors; D005472:Fluorouracil; D019394:Ki-67 Antigen; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000097245:Ursolic Acid