PMID- 21875325
OWN - NLM
STAT- MEDLINE
DCOM- 20120202
LR  - 20220317
IS  - 1532-7914 (Electronic)
IS  - 0163-5581 (Print)
IS  - 0163-5581 (Linking)
VI  - 63
IP  - 7
DP  - 2011
TI  - Sulforaphane potentiates the efficacy of 17-allylamino 17-demethoxygeldanamycin 
      against pancreatic cancer through enhanced abrogation of Hsp90 chaperone 
      function.
PG  - 1151-9
LID - 10.1080/01635581.2011.596645 [doi]
AB  - 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.
FAU - Li, Yanyan
AU  - Li Y
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Michigan, Ann Arbor, Michigan 48109, USA.
FAU - Zhang, Tao
AU  - Zhang T
FAU - Schwartz, Steven J
AU  - Schwartz SJ
FAU - Sun, Duxin
AU  - Sun D
LA  - eng
GR  - P30 CA016058/CA/NCI NIH HHS/United States
GR  - R01 CA120023/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110829
PL  - United States
TA  - Nutr Cancer
JT  - Nutrition and cancer
JID - 7905040
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzoquinones)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Isothiocyanates)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Plant Extracts)
RN  - 0 (Sulfoxides)
RN  - 0 (Thiocyanates)
RN  - 4GY0AVT3L4 (tanespimycin)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - GA49J4310U (sulforaphane)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Benzoquinones/*pharmacology
MH  - Blotting, Western
MH  - Brassica/chemistry
MH  - Caspase 3/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors/*genetics/metabolism
MH  - Humans
MH  - Immunoprecipitation
MH  - Isothiocyanates
MH  - Lactams, Macrocyclic/*pharmacology
MH  - Mice
MH  - Mice, Nude
MH  - Pancreatic Neoplasms/metabolism
MH  - Plant Extracts/*pharmacology
MH  - Sulfoxides
MH  - Thiocyanates/*pharmacology
PMC - PMC3850054
MID - NIHMS526370
EDAT- 2011/08/31 06:00
MHDA- 2012/02/03 06:00
PMCR- 2013/12/04
CRDT- 2011/08/31 06:00
PHST- 2011/08/31 06:00 [entrez]
PHST- 2011/08/31 06:00 [pubmed]
PHST- 2012/02/03 06:00 [medline]
PHST- 2013/12/04 00:00 [pmc-release]
AID - 10.1080/01635581.2011.596645 [doi]
PST - ppublish
SO  - Nutr Cancer. 2011;63(7):1151-9. doi: 10.1080/01635581.2011.596645. Epub 2011 Aug 
      29.