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dc.contributor.authorAlqurashi, Naif
dc.contributor.authorHashimi, Saeed M
dc.contributor.authorAlowaidi, Faisal
dc.contributor.authorIvanovski, Saso
dc.contributor.authorWei, Ming Q
dc.date.accessioned2019-06-08T01:33:13Z
dc.date.available2019-06-08T01:33:13Z
dc.date.issued2018
dc.identifier.issn1021-335X
dc.identifier.doi10.3892/or.2018.6457
dc.identifier.urihttp://hdl.handle.net/10072/383242
dc.description.abstractThe 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherSPANDIDOS PUBL LTD
dc.relation.ispartofpagefrom1083
dc.relation.ispartofpageto1092
dc.relation.ispartofissue2
dc.relation.ispartofjournalONCOLOGY REPORTS
dc.relation.ispartofvolume40
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchcode3211
dc.titleDual mTOR/PI3K inhibitor NVP-BEZ235 arrests colorectal cancer cell growth and displays differential inhibition of 4E-BP1
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorWei, Ming Q.


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