PMID- 18252805
OWN - NLM
STAT- MEDLINE
DCOM- 20080506
LR  - 20211020
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 73
IP  - 5
DP  - 2008 May
TI  - The chemopreventive agent curcumin is a potent radiosensitizer of human cervical 
      tumor cells via increased reactive oxygen species production and overactivation 
      of the mitogen-activated protein kinase pathway.
PG  - 1491-501
LID - 10.1124/mol.107.043554 [doi]
AB  - Cervical cancer is the second most common malignancy among women worldwide and is 
      highly radioresistant, often resulting in local treatment failure. For locally 
      advanced disease, radiation is combined with low-dose chemotherapy; however, this 
      modality often leads to severe toxicity. Curcumin, a polyphenol extracted from 
      rhizomes of the plant Curcuma longa, is a widely studied chemopreventive agent 
      that was shown to have a low toxicity profile in three human clinical trials. 
      Here, we show that pretreatment of two cervical carcinoma cell lines, HeLa and 
      SiHa, with curcumin before ionizing radiation (IR) resulted in significant 
      dose-dependent radiosensitization of these cells. It is noteworthy that curcumin 
      failed to radiosensitize normal human diploid fibroblasts. Although in tumor 
      cells, curcumin did not significantly affect IR-induced activation of AKT and 
      nuclear factor-kappaB, we found that it caused a significant increase in the 
      production of reactive oxygen species, which further led to sustained 
      extracellular signal-regulated kinase (ERK) 1/2 activation. The antioxidant 
      compound N-acetylcysteine blocked the curcumin-induced increased reactive oxygen 
      species (ROS), sustained activation of ERK1/2, and decreased survival after IR in 
      HeLa cells, implicating a ROS-dependent mechanism for curcumin radiosensitivity. 
      Moreover, PD98059 (2'-amino-3'-methoxyflavone)-, PD184352- 
      [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], 
      and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynylthio)butadiene]-specific 
      inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) blocked 
      curcumin-mediated radiosensitization, demonstrating that the sustained ERK1/2 
      activation resulting from ROS generation leads to curcumin-mediated 
      radiosensitization. Together, these results suggest a novel mechanism for 
      curcumin-mediated radiosensitization involving increased ROS and ERK1/2 
      activation and suggest that curcumin application (either systemically or 
      topically) may be an effective radiation modifying modality in the treatment of 
      cervical cancer.
FAU - Javvadi, Prashanthi
AU  - Javvadi P
AD  - Department of Radiation Oncology, University of Pennsylvania, 3620 Hamilton Walk, 
      Philadelphia, PA 19104, USA.
FAU - Segan, Andrew T
AU  - Segan AT
FAU - Tuttle, Stephen W
AU  - Tuttle SW
FAU - Koumenis, Constantinos
AU  - Koumenis C
LA  - eng
GR  - R01 CA104922/CA/NCI NIH HHS/United States
GR  - R01 CA104922-03/CA/NCI NIH HHS/United States
GR  - R01-CA104922/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080205
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (NF-kappa B)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - IT942ZTH98 (Curcumin)
SB  - IM
MH  - Apoptosis/drug effects/radiation effects
MH  - *Chemoprevention
MH  - Curcumin/*pharmacology
MH  - Drug Synergism
MH  - Enzyme Activation/drug effects/radiation effects
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - HeLa Cells
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects/radiation effects
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Models, Biological
MH  - NF-kappa B/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Radiation Tolerance/drug effects/radiation effects
MH  - Radiation, Ionizing
MH  - Radiation-Sensitizing Agents/*pharmacology
MH  - Reactive Oxygen Species/*metabolism
MH  - Uterine Cervical Neoplasms/*enzymology/*pathology
PMC - PMC3400533
MID - NIHMS317297
EDAT- 2008/02/07 09:00
MHDA- 2008/05/07 09:00
PMCR- 2012/07/19
CRDT- 2008/02/07 09:00
PHST- 2008/02/07 09:00 [pubmed]
PHST- 2008/05/07 09:00 [medline]
PHST- 2008/02/07 09:00 [entrez]
PHST- 2012/07/19 00:00 [pmc-release]
AID - mol.107.043554 [pii]
AID - 10.1124/mol.107.043554 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2008 May;73(5):1491-501. doi: 10.1124/mol.107.043554. Epub 2008 
      Feb 5.