PMID- 23908594
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20211021
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 15
IP  - 8
DP  - 2013 Aug
TI  - Flavopiridol synergizes with sorafenib to induce cytotoxicity and potentiate 
      antitumorigenic activity in EGFR/HER-2 and mutant RAS/RAF breast cancer model 
      systems.
PG  - 939-51
AB  - Oncogenic receptor tyrosine kinase (RTK) signaling through the Ras-Raf-Mek-Erk 
      (Ras-MAPK) pathway is implicated in a wide array of carcinomas, including those 
      of the breast. The cyclin-dependent kinases (CDKs) are implicated in regulating 
      proliferative and survival signaling downstream of this pathway. Here, we show 
      that CDK inhibitors exhibit an order of magnitude greater cytotoxic potency than 
      a suite of inhibitors targeting RTK and Ras-MAPK signaling in cell lines 
      representative of clinically recognized breast cancer (BC) subtypes. Drug 
      combination studies show that the pan-CDK inhibitor, flavopiridol (FPD), 
      synergistically potentiated cytotoxicity induced by the Raf inhibitor, sorafenib 
      (SFN). This synergy was most pronounced at sub-EC50 SFN concentrations in 
      MDA-MB-231 (KRAS-G13D and BRAF-G464V mutations), MDA-MB-468 [epidermal growth 
      factor receptor (EGFR) overexpression], and SKBR3 [ErbB2/EGFR2 (HER-2) 
      overexpression] cells but not in hormone-dependent MCF-7 and T47D cells. 
      Potentiation of SFN cytotoxicity by FPD correlated with enhanced apoptosis, 
      suppression of retinoblastoma (Rb) signaling, and reduced Mcl-1 expression. SFN 
      and FPD were also tested in an MDA-MB-231 mammary fat pad engraftment model of 
      tumorigenesis. Mice treated with both drugs exhibited reduced primary tumor 
      growth rates and metastatic tumor load in the lungs compared to treatment with 
      either drug alone, and this correlated with greater reductions in Rb signaling 
      and Mcl-1 expression in resected tumors. These findings support the development 
      of CDK and Raf co-targeting strategies in EGFR/HER-2-overexpressing or RAS/RAF 
      mutant BCs.
FAU - Nagaria, Teddy S
AU  - Nagaria TS
AD  - Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 
      Queen's University, Kingston, Ontario, Canada.
FAU - Williams, Julia L
AU  - Williams JL
FAU - Leduc, Charles
AU  - Leduc C
FAU - Squire, Jeremy A
AU  - Squire JA
FAU - Greer, Peter A
AU  - Greer PA
FAU - Sangrar, Waheed
AU  - Sangrar W
LA  - eng
GR  - 219762/Canadian Institutes of Health Research/Canada
GR  - 219806/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Flavonoids)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Piperidines)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 45AD6X575G (alvocidib)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (raf Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Breast Neoplasms/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cyclin-Dependent Kinases/antagonists & inhibitors/metabolism
MH  - Drug Synergism
MH  - ErbB Receptors/metabolism
MH  - Female
MH  - Flavonoids/administration & dosage/*pharmacology
MH  - Humans
MH  - Lung Neoplasms/prevention & control/secondary
MH  - MCF-7 Cells
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - Mutation
MH  - Niacinamide/administration & dosage/*analogs & derivatives/pharmacology
MH  - Phenylurea Compounds/administration & dosage/*pharmacology
MH  - Piperidines/administration & dosage/*pharmacology
MH  - Receptor, ErbB-2/metabolism
MH  - Sorafenib
MH  - Treatment Outcome
MH  - Tumor Burden/drug effects
MH  - *Xenograft Model Antitumor Assays
MH  - raf Kinases/antagonists & inhibitors/genetics/metabolism
MH  - ras Proteins/antagonists & inhibitors/genetics/metabolism
PMC - PMC3730045
EDAT- 2013/08/03 06:00
MHDA- 2014/03/04 06:00
PMCR- 2013/08/01
CRDT- 2013/08/03 06:00
PHST- 2013/04/10 00:00 [received]
PHST- 2013/05/27 00:00 [revised]
PHST- 2013/05/31 00:00 [accepted]
PHST- 2013/08/03 06:00 [entrez]
PHST- 2013/08/03 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2013/08/01 00:00 [pmc-release]
AID - 13804 [pii]
AID - 10.1593/neo.13804 [doi]
PST - ppublish
SO  - Neoplasia. 2013 Aug;15(8):939-51. doi: 10.1593/neo.13804.