PURPOSE: Current treatments for metastatic RCC (mRCC) do not extend survival beyond a few months.
Sorafenib (SF) is a targeted drug approved for mRCC, but it has modest efficacy. Hymecromone is a nontoxic dietary supplement with some antitumor activity at high doses (450 - 3000 mg/day). HC inhibits hyaluronic acid (HA) synthesis. HA promotes tumor growth and metastasis. We recently showed that HA-receptors CD44 and RHAMM are potential predictors of mRCC. We examined the anti-tumor properties of HC, SF, and their combination in RCC models.
METHODS: Using proliferation, clonogenic and apoptosis assays, effects of HC (0-32 μg/ml), SF (0-3.2 μg/ml) and HC+SF were examined in RCC cells (Caki-1, 786-O, ACHN, A498) and endothelial cells (HMVEC-L, HUVEC). Boyden chamber was used for motility and invasion assays. Apoptosis indicators, HA receptors, EGFR and c-Met were evaluated by immunoblotting. Efficacy of HC, SF and HC+SF was evaluated in the SF-resistant Caki-1 xenograft model.
RESULTS: HC+SF synergistically inhibited proliferation (>95%), motility/invasion (65%) and capillary formation (76%) in RCC and/or endothelial cells, and induced apoptosis by 8-fold (P< 0.001). HC+SF inhibited HA synthesis and HA addition reversed the cytotoxicity of HC+SF. HC+SF up-regulated pro-apoptotic indicators and downregulated Mcl-1, CD44, RHAMM, phospho-EGFR and phospho-cMet levels. In all assays, HC and SF alone were ineffective. Oral administration of HC (50-200mg/kg) plus SF (30mg/kg) eradicated Caki-1 tumor growth without toxicity. HC and SF alone were ineffective.
CONCLUSION: This is the first study that demonstrates combination of SF with HC a non-toxic dietary supplement is highly effective in controlling RCC.
Written by:
Benitez A, Yates TJ, Shamaldevi N, Bowen T, Lokeshwar VB. Are you the author?
Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, Florida 33101.
Reference: J Urol. 2012 Dec 7. pii: S0022-5347(12)05835-1.
doi: 10.1016/j.juro.2012.12.011
PubMed Abstract
PMID: 23228386
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