PMID- 24729100
OWN - NLM
STAT- MEDLINE
DCOM- 20150422
LR  - 20231213
IS  - 1573-675X (Electronic)
IS  - 1360-8185 (Linking)
VI  - 19
IP  - 7
DP  - 2014 Jul
TI  - Piperlongumine, an alkaloid causes inhibition of PI3 K/Akt/mTOR signaling axis to 
      induce caspase-dependent apoptosis in human triple-negative breast cancer cells.
PG  - 1148-64
LID - 10.1007/s10495-014-0991-2 [doi]
AB  - The phosphatidylinositol 3-kinase (PI3 K)/Akt/mammalian target of rapamycin 
      (mTOR) signaling axis plays a central role in cell proliferation, growth and 
      survival under physiological conditions. However, aberrant PI3 K/Akt/mTOR 
      signaling has been implicated in many human cancers, including human triple 
      negative breast cancer. Therefore, dual inhibitors of PI3 K/Akt and mTOR 
      signaling could be valuable agents for treating breast cancer. The objective of 
      this study was to investigate the effect of piperlongumine (PPLGM), a natural 
      alkaloid on PI3 K/Akt/mTOR signaling, Akt mediated regulation of NF-kB and 
      apoptosis evasion in human breast cancer cells. Using molecular docking studies, 
      we found that PPLGM physically interacts with the conserved domain of PI3 K and 
      mTOR kinases and the results were comparable with standard dual inhibitor 
      PF04691502. Our results demonstrated that treatment of different human 
      triple-negative breast cancer cells with PPLGM resulted in concentration- and 
      time-dependent growth inhibition. The inhibition of cancer cell growth was 
      associated with G1-phase cell cycle arrest and down-regulation of the NF-kB 
      pathway leads to activation of the mitochondrial apoptotic pathway. It was also 
      found that PPLGM significantly decreased the expression of p-Akt, p70S6K1, 
      4E-BP1, cyclin D1, Bcl-2, p53 and increased expression of Bax, cytochrome c in 
      human triple-negative breast cancer cells. Although insulin treatment increased 
      the phosphorylation of Akt (Ser473), p70S6K1, 4E-BP1, PPLGM abolished the insulin 
      mediated phosphorylation, it clearly indicates that PPLGM acts through 
      PI3 k/Akt/mTOR axis. Our results suggest that PPLGM may be an effective 
      therapeutic agent for the treatment of human triple negative breast cancer.
FAU - Shrivastava, Shweta
AU  - Shrivastava S
AD  - Department of Pharmacology & Toxicology, National Institute of Pharmaceutical 
      Education & Research (NIPER-Hyderabad), Balanagar, Hyderabad, 500037, A.P, India.
FAU - Kulkarni, Prasad
AU  - Kulkarni P
FAU - Thummuri, Dinesh
AU  - Thummuri D
FAU - Jeengar, Manish Kumar
AU  - Jeengar MK
FAU - Naidu, V G M
AU  - Naidu VG
FAU - Alvala, Mallika
AU  - Alvala M
FAU - Redddy, G Bhanuprakash
AU  - Redddy GB
FAU - Ramakrishna, Sistla
AU  - Ramakrishna S
LA  - eng
PT  - Journal Article
PL  - Netherlands
TA  - Apoptosis
JT  - Apoptosis : an international journal on programmed cell death
JID - 9712129
RN  - 0 (Alkaloids)
RN  - 0 (Dioxolanes)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Caspases)
RN  - SGD66V4SVJ (piperlongumine)
SB  - IM
MH  - Alkaloids/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Caspases/*metabolism
MH  - Cell Cycle Checkpoints/drug effects/genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - DNA Fragmentation/drug effects
MH  - Dioxolanes/*pharmacology
MH  - Female
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Phosphatidylinositol 3-Kinase/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Triple Negative Breast Neoplasms/*metabolism/pathology
EDAT- 2014/04/15 06:00
MHDA- 2015/04/23 06:00
CRDT- 2014/04/15 06:00
PHST- 2014/04/15 06:00 [entrez]
PHST- 2014/04/15 06:00 [pubmed]
PHST- 2015/04/23 06:00 [medline]
AID - 10.1007/s10495-014-0991-2 [doi]
PST - ppublish
SO  - Apoptosis. 2014 Jul;19(7):1148-64. doi: 10.1007/s10495-014-0991-2.