PURPOSE: 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. MATERIALS AND 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.
PURPOSE: 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. MATERIALS AND 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-1tumor 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: Andrew Chi; Samir P Shirodkar; Diogo O Escudero; Obi O Ekwenna; Travis J Yates; Rajinikanth Ayyathurai; Michael Garcia-Roig; Jeffrey C Gahan; Murugesan Manoharan; Vincent G Bird; Vinata B Lokeshwar Journal: Cancer Date: 2011-09-01 Impact factor: 6.860
Authors: José Ángel Arranz; Miguel Ángel Climent; José Luis González-Larriba; Luis León; José Pablo Maroto Journal: Crit Rev Oncol Hematol Date: 2011-03-21 Impact factor: 6.312
Authors: Anne Kultti; Sanna Pasonen-Seppänen; Marjo Jauhiainen; Kirsi J Rilla; Riikka Kärnä; Emma Pyöriä; Raija H Tammi; Markku I Tammi Journal: Exp Cell Res Date: 2009-03-13 Impact factor: 3.905
Authors: Raija H Tammi; Anne Kultti; Veli-Matti Kosma; Risto Pirinen; Päivi Auvinen; Markku I Tammi Journal: Semin Cancer Biol Date: 2008-03-26 Impact factor: 15.707
Authors: E Arai; Y Nishida; J Wasa; H Urakawa; L Zhuo; K Kimata; E Kozawa; N Futamura; N Ishiguro Journal: Br J Cancer Date: 2011-11-01 Impact factor: 7.640
Authors: Essa M Bajalia; Farah B Azzouz; Danielle A Chism; Derrek M Giansiracusa; Carina G Wong; Kristina N Plaskett; Anupam Bishayee Journal: Cancers (Basel) Date: 2022-07-04 Impact factor: 6.575
Authors: Rahul K Lall; Deeba N Syed; Mohammad Imran Khan; Vaqar M Adhami; Yuansheng Gong; John A Lucey; Hasan Mukhtar Journal: Carcinogenesis Date: 2016-06-22 Impact factor: 4.944
Authors: Larry House; Michael J Seminerio; Snezana Mirkov; Jacqueline Ramirez; Maxwell Skor; Joseph R Sachleben; Masis Isikbay; Hari Singhal; Geoffrey L Greene; Donald Vander Griend; Suzanne D Conzen; Mark J Ratain Journal: Xenobiotica Date: 2017-11-10 Impact factor: 1.908
Authors: Travis J Yates; Luis E Lopez; Soum D Lokeshwar; Nicolas Ortiz; Georgios Kallifatidis; Andre Jordan; Kelly Hoye; Norman Altman; Vinata B Lokeshwar Journal: J Natl Cancer Inst Date: 2015-04-13 Impact factor: 13.506
Authors: Carla N Olivares; Laura D Alaniz; Michael D Menger; Rosa I Barañao; Matthias W Laschke; Gabriela F Meresman Journal: PLoS One Date: 2016-03-28 Impact factor: 3.240
Authors: Andre R Jordan; Jiaojiao Wang; Travis J Yates; Sarrah L Hasanali; Soum D Lokeshwar; Daley S Morera; Nagarajarao Shamaladevi; Charles S Li; Zachary Klaassen; Martha K Terris; Muthusamy Thangaraju; Amar B Singh; Mark S Soloway; Vinata B Lokeshwar Journal: Oncogenesis Date: 2020-05-19 Impact factor: 7.485