PMID- 29845289
OWN - NLM
STAT- MEDLINE
DCOM- 20181012
LR  - 20211204
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 40
IP  - 2
DP  - 2018 Aug
TI  - Dual mTOR/PI3K inhibitor NVP‑BEZ235 arrests colorectal cancer cell growth and 
      displays differential inhibition of 4E‑BP1.
PG  - 1083-1092
LID - 10.3892/or.2018.6457 [doi]
AB  - The mammalian target of rapamycin (mTOR), a downstream effector of the PI3K/Akt 
      signalling pathway, is a critical regulator of cell metabolism, growth and 
      survival in response to oncogenic factors. Activation of mTOR frequently occurs 
      in human tumours making it a crucial and validated target in the treatment of 
      cancer. mTOR inhibitors such as rapamycin and its analogues decrease cancer 
      progression in experimental models including colorectal cancer (CRC). Recently, 
      the second generation ATP‑competitive mTOR kinase (such as PP242) and dual 
      mTOR/PI3K (such as NVP‑BEZ235) inhibitors have entered clinical trials as 
      anticancer agents. However, in CRC, the efficacy of these novel drugs needs to be 
      fully investigated. In the present study, we examined five human CRC cell lines, 
      HT29, HCT116, SW480, SW620 and CSC480 to evaluate their sensitivity to three mTOR 
      inhibitors, RAD001, PP242 and NVP‑BEZ235. We observed that compared to RAD001 and 
      PP242, NVP‑BEZ235 markedly reduced cell proliferation of CRC cells. Furthermore, 
      we found that the reduced cell proliferation caused by NVP‑BEZ235 was not 
      achieved through the disruption of mitochondrial potential. Using an 
      mTOR‑specific signalling pathway phospho array we revealed that NVP‑BEZ235 
      significantly decreased phosphorylation of 4E‑BP1 (Thr70), the downstream target 
      of mTORC1. In addition, NVP‑BEZ235 decreased phosphorylation of AKT (Ser473), the 
      downstream target of mTORC2. Immunoblotting analysis revealed that NVP‑BEZ235 
      effectively inhibited 4E‑BP1 phosphorylation, while PP242 had a weak inhibitory 
      effect. However, PP242 and NVP‑BEZ235 decreased AKT levels in all cell lines. 
      RAD001 demonstrated no effect on 4E‑BP1. Based on the above‑mentioned results, 
      the dual PI3K/mTOR and ATP‑competitive mTOR inhibitors have demonstrated high 
      potential for targeting the mTOR pathway in CRC.
FAU - Alqurashi, Naif
AU  - Alqurashi N
AD  - Department of Basic Sciences, Deanship of Preparatory Studies, Imam Abdulrahman 
      Bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia.
FAU - Hashimi, Saeed M
AU  - Hashimi SM
AD  - Department of Basic Sciences, Deanship of Preparatory Studies, Imam Abdulrahman 
      Bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia.
FAU - Alowaidi, Faisal
AU  - Alowaidi F
AD  - Department of Pathology and Laboratory Medicine, College of Medicine and 
      University Hospitals, King Saud University, Riyadh 11461, Kingdom of Saudi 
      Arabia.
FAU - Ivanovski, Saso
AU  - Ivanovski S
AD  - School of Medical Science and Menzies Health Institute Queensland, Griffith 
      University, Gold Coast, Queensland 4333, Australia.
FAU - Wei, Ming Q
AU  - Wei MQ
AD  - School of Medical Science and Menzies Health Institute Queensland, Griffith 
      University, Gold Coast, Queensland 4333, Australia.
LA  - eng
PT  - Journal Article
DEP - 20180522
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Purines)
RN  - 0 (Quinolines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*antagonists & inhibitors
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Colorectal Neoplasms/*drug therapy/metabolism
MH  - Everolimus/pharmacology
MH  - HCT116 Cells
MH  - HT29 Cells
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Indoles/pharmacology
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoproteins/*antagonists & inhibitors
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Purines/pharmacology
MH  - Quinolines/*pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
EDAT- 2018/05/31 06:00
MHDA- 2018/10/13 06:00
CRDT- 2018/05/31 06:00
PHST- 2017/11/13 00:00 [received]
PHST- 2018/04/11 00:00 [accepted]
PHST- 2018/05/31 06:00 [pubmed]
PHST- 2018/10/13 06:00 [medline]
PHST- 2018/05/31 06:00 [entrez]
AID - 10.3892/or.2018.6457 [doi]
PST - ppublish
SO  - Oncol Rep. 2018 Aug;40(2):1083-1092. doi: 10.3892/or.2018.6457. Epub 2018 May 22.