PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas

  • Authors:
    • Deyu Chen
    • Chaoming Mao
    • Yuepeng Zhou
    • Yuting Su
    • Shenzha Liu
    • Wen-Qing Qi
  • View Affiliations

  • Published online on: November 5, 2015     https://doi.org/10.3892/ijo.2015.3231
  • Pages: 253-260
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Abstract

The PI3K/Akt/mTOR pathway is activated in a variety of human tumors including B-cell non-Hodgkin lymphoma (B-NHL). Targeting this pathway has been validated in solid and hematological tumors. In the present study, we demonstrated that PF-04691502, a novel PI3K/mTOR inhibitor has potent activity in a panel of aggressive B-NHL cell lines including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). MTS analysis showed that PF-04691502 effectively inhibited cell proliferation with IC50 values ranging from 0.12 to 0.55 µM. Cells treated with PF-04691502 exhibited decreased phosphorylation of Akt and S6 ribosomal protein confirming the mechanism of action of a PI3K/mTOR inhibitor. Also, treatment of B-NHL cell lines with PF-04691502 induced apoptosis in a dose- and time-dependent manner. Moreover, PF-04691502 significantly induced G1 cell cycle arrest associated with a decrease in cyclin D1 which contributed to suppression of cell proliferation. Finally, rituximab enhanced apoptosis induced by PF-04691502. Taken together, our findings provide for the first time that PF-04691502 inhibits the constitutively activated PI3K/mTOR pathway in aggressive B-cell NHL cell lines associated with inhibition of cell cycle progression, cell proliferation and promotion of apoptosis. These findings suggest that PF-04691502 is a novel therapeutic strategy in aggressive B-cell NHL and warrants early phase clinical trial evaluation with and without rituximab.
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January-2016
Volume 48 Issue 1

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Spandidos Publications style
Chen D, Mao C, Zhou Y, Su Y, Liu S and Qi W: PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas. Int J Oncol 48: 253-260, 2016
APA
Chen, D., Mao, C., Zhou, Y., Su, Y., Liu, S., & Qi, W. (2016). PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas. International Journal of Oncology, 48, 253-260. https://doi.org/10.3892/ijo.2015.3231
MLA
Chen, D., Mao, C., Zhou, Y., Su, Y., Liu, S., Qi, W."PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas". International Journal of Oncology 48.1 (2016): 253-260.
Chicago
Chen, D., Mao, C., Zhou, Y., Su, Y., Liu, S., Qi, W."PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas". International Journal of Oncology 48, no. 1 (2016): 253-260. https://doi.org/10.3892/ijo.2015.3231