PMID- 23343191
OWN - NLM
STAT- MEDLINE
DCOM- 20140110
LR  - 20211021
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 13
DP  - 2013 Jan 23
TI  - Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by 
      cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer 
      cells.
PG  - 29
LID - 10.1186/1471-2407-13-29 [doi]
AB  - BACKGROUND: In the present study, we show that the combination of doxorubicin 
      with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal 
      doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces 
      extensive apoptosis than either drug alone in H-460 human NSCLC cells. METHODS: 
      Synergistic effects of P276-00 and doxorubicin on growth inhibition was studied 
      using the Propidium Iodide (PI) assay. The doses showing the best synergistic 
      effect was determined and these doses were used for further mechanistic studies 
      such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of 
      the combination was evaluated using the H-460 xenograft model. RESULTS: The 
      combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic 
      effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively 
      as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced 
      G2/M arrest and induction of apoptosis was observed in the combination treatment. 
      This was associated with induction of tumor suppressor protein p53 and reduction 
      of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced 
      COX-2, a NF-kappaB target and Cdk-1, a target of P276-00, which was downregulated by 
      P276-00 in the combination. Doxorubicin when combined with P276-00 in a 
      sequence-specific manner significantly inhibited tumor growth, compared with 
      either doxorubicin or P276-00 alone in H-460 xenograft model. CONCLUSION: These 
      findings suggest that this combination may increase the therapeutic index over 
      doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an 
      inhibition of doxorubicin-induced chemoresistance involving NF-kappaB signaling and 
      inhibition of Cdk-1 which is involved in cell cycle progression.
FAU - Rathos, Maggie J
AU  - Rathos MJ
AD  - Oncology Franchise, Piramal Healthcare Limited, 1-Nirlon Complex, Goregaon, 
      Mumbai 400 063, India.
FAU - Khanwalkar, Harshal
AU  - Khanwalkar H
FAU - Joshi, Kavita
AU  - Joshi K
FAU - Manohar, Sonal M
AU  - Manohar SM
FAU - Joshi, Kalpana S
AU  - Joshi KS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130123
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Flavones)
RN  - 0 (NF-kappa B)
RN  - 0 (P276-00)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 2.7.11.22 (CDC2 Protein Kinase)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/*therapeutic use
MH  - Apoptosis/drug effects
MH  - CDC2 Protein Kinase/metabolism
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cyclooxygenase 2/metabolism
MH  - Doxorubicin/administration & dosage
MH  - Drug Synergism
MH  - Flavones/administration & dosage
MH  - G2 Phase Cell Cycle Checkpoints/drug effects
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/genetics
MH  - Mice
MH  - Mice, SCID
MH  - NF-kappa B/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Tumor Suppressor Protein p53/genetics
PMC - PMC3635914
EDAT- 2013/01/25 06:00
MHDA- 2014/01/11 06:00
PMCR- 2013/01/23
CRDT- 2013/01/25 06:00
PHST- 2012/09/13 00:00 [received]
PHST- 2013/01/16 00:00 [accepted]
PHST- 2013/01/25 06:00 [entrez]
PHST- 2013/01/25 06:00 [pubmed]
PHST- 2014/01/11 06:00 [medline]
PHST- 2013/01/23 00:00 [pmc-release]
AID - 1471-2407-13-29 [pii]
AID - 10.1186/1471-2407-13-29 [doi]
PST - epublish
SO  - BMC Cancer. 2013 Jan 23;13:29. doi: 10.1186/1471-2407-13-29.