title: Dietary supplement hymecromone and sorafenib: a novel combination for the control of renal cell carcinoma.
abstract: OBJECTIVE
  Current treatments for metastatic renal cell carcinoma do not extend survival beyond a few months. Sorafenib is a targeted drug approved for metastatic renal cell carcinoma but it has modest efficacy. Hymecromone is a nontoxic dietary supplement with some antitumor activity at high doses of 450 to 3,000 mg per day. Hymecromone inhibits the synthesis of hyaluronic acid, which promotes tumor growth and metastasis. We recently noted that the hyaluronic acid receptors CD44 and RHAMM are potential predictors of metastatic renal cell carcinoma. In the current study we examined the antitumor properties of hymecromone, sorafenib and the combination in renal cell carcinoma models.
  
  
  METHODS
  Using proliferation, clonogenic and apoptosis assays, we examined the effects of hymecromone (0 to 32 μg/ml), sorafenib (0 to 3.2 μg/ml) and hymecromone plus sorafenib in Caki-1, 786-O, ACHN and A498 renal cell carcinoma cells, and HMVEC-L and HUVEC endothelial cells. A Boyden chamber was used for motility and invasion assays. Apoptosis indicators, hyaluronic acid receptors, epidermal growth factor receptor and c-Met were evaluated by immunoblot. The efficacy of hymecromone, sorafenib and hymecromone plus sorafenib was assessed in the sorafenib resistant Caki-1 xenograft model.
  
  
  RESULTS
  Hymecromone plus sorafenib synergistically inhibited proliferation (greater than 95%), motility/invasion (65%) and capillary formation (76%) in renal cell carcinoma and/or endothelial cells, and induced apoptosis eightfold (p <0.001). Hymecromone plus sorafenib inhibited hyaluronic acid synthesis and adding hyaluronic acid reversed the cytotoxicity of hymecromone plus sorafenib. Hymecromone plus sorafenib up-regulated pro-apoptotic indicators and down-regulated Mcl-1, CD44, RHAMM, phospho-epidermal growth factor receptor and phospho-cMet. In all assays hymecromone and sorafenib alone were ineffective. Oral administration of hymecromone (50 to 200 mg/kg) plus sorafenib (30 mg/kg) eradicated Caki-1 tumor growth without toxicity. Hymecromone and sorafenib alone were ineffective.
  
  
  CONCLUSIONS
  To our knowledge this is the first study to show that the combination of sorafenib and the nontoxic dietary supplement hymecromone is highly effective for controlling renal cell carcinoma.
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, Florida 33101, USA.
authors.forename: Anaid
authors.initials: A
authors.lastname: Benitez
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Yates
authors.forename: N
authors.initials: N
authors.lastname: Shamaldevi
authors.forename: Tim
authors.initials: T
authors.lastname: Bowen
authors.forename: Vinata B
authors.initials: VB
authors.lastname: Lokeshwar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006923:Hymecromone / Q000494:pharmacology*; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000077157:Sorafenib; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D006923:Hymecromone; D000077157:Sorafenib