Dual mTOR/PI3K inhibitor NVP‑BEZ235 arrests colorectal cancer cell growth and displays differential inhibition of 4E‑BP1

Alqurashi,Naif; Hashimi,Saeed M.; Alowaidi,Faisal; Ivanovski,Saso; Wei,Ming Q.

doi:10.3892/or.2018.6457

Dual mTOR/PI3K inhibitor NVP‑BEZ235 arrests colorectal cancer cell growth and displays differential inhibition of 4E‑BP1

Authors:
- Naif Alqurashi
- Saeed M. Hashimi
- Faisal Alowaidi
- Saso Ivanovski
- Ming Q. Wei
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Affiliations: Department of Basic Sciences, Deanship of Preparatory Studies, Imam Abdulrahman Bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia, Department of Pathology and Laboratory Medicine, College of Medicine and University Hospitals, King Saud University, Riyadh 11461, Kingdom of Saudi Arabia, School of Medical Science and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland 4333, Australia
Published online on: May 22, 2018 https://doi.org/10.3892/or.2018.6457
Pages: 1083-1092

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Abstract

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.

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