Sulforaphane potentiates the efficacy of 17-allylamino 17-demethoxygeldanamycin against pancreatic cancer through enhanced abrogation of Hsp90 chaperone function.

Abstract	Heat shock protein 90 (Hsp90), an essential molecular chaperone that regulates the stability of a wide range of oncogenic proteins, is a promising target for cancer therapeutics. We investigated the combination efficacy and potential mechanisms of sulforaphane, a dietary component from broccoli and broccoli sprouts, and 17-allylamino 17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, in pancreatic cancer. MTS assay demonstrated that sulforaphane sensitized pancreatic cancer cells to 17-AAG in vitro. Caspase-3 was activated to 6.4-fold in response to simultaneous treatment with sulforaphane and 17-AAG, whereas 17-AAG alone induced caspase-3 activity to 2-fold compared to control. ATP binding assay and coimmunoprecipitation revealed that sulforaphane disrupted Hsp90-p50(Cdc37) interaction, whereas 17-AAG inhibited ATP binding to Hsp90. Concomitant use of sulforaphane and 17-AAG synergistically downregulated Hsp90 client proteins in Mia Paca-2 cells. Co-administration of sulforaphane and 17-AAG in pancreatic cancer xenograft model led to more than 70% inhibition of the tumor growth, whereas 17-AAG alone only suppressed the tumor growth by 50%. Our data suggest that sulforaphane potentiates the efficacy of 17-AAG against pancreatic cancer through enhanced abrogation of Hsp90 function. These findings provide a rationale for further evaluation of broccoli/broccoli sprout preparations combined with 17-AAG for better efficacy and lower dose-limiting toxicity in pancreatic cancer.
Authors	Yanyan Li, Tao Zhang, Steven J Schwartz, Duxin Sun
Journal	Nutrition and cancer (Nutr Cancer) Vol. 63 Issue 7 Pg. 1151-9 ( 2011) ISSN: 1532-7914 [Electronic] United States
PMID	21875325 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Benzoquinones HSP90 Heat-Shock Proteins Isothiocyanates Lactams, Macrocyclic Plant Extracts Sulfoxides Thiocyanates tanespimycin CASP3 protein, human Caspase 3 sulforaphane
Topics	Animals Antineoplastic Agents (pharmacology) Benzoquinones (pharmacology) Blotting, Western Brassica (chemistry) Caspase 3 (genetics, metabolism) Cell Line, Tumor Drug Synergism Female Gene Expression Regulation, Neoplastic HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism) Humans Immunoprecipitation Isothiocyanates Lactams, Macrocyclic (pharmacology) Mice Mice, Nude Pancreatic Neoplasms (metabolism) Plant Extracts (pharmacology) Sulfoxides Thiocyanates (pharmacology)

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