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Anticancer Res. 2015 May;35(5):2699-708.

Combining CAL-101 with Celecoxib Enhances Apoptosis of EBV-transformed B-Cells Through MAPK-induced ER Stress.

Author information

1
Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea.
2
Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea kimdj@inje.ac.kr.

Abstract

BACKGROUND:

Phosphoinositide-3 kinase (PI3K) inhibition attenuates proliferation and survival in B-cell malignancies. Celecoxib induces endoplasmic reticulum (ER) stress-induced apoptosis via a cyclo-oxgenase-2 (COX2)-independent manner in certain types of cancer cells. In the present study, we assessed the effects of combinations of drugs with a p110δ-specific inhibitor, CAL-101, and celecoxib to induce apoptosis in Epstein-Barr virus (EBV)-transformed B-cells and non-Hodgkin's lymphoma (NHL) cells.

MATERIALS AND METHODS:

The apoptotic effect of combination treatment with CAL-101 and celecoxib on B-cell malignancies was determined by flow cytometry and immunoblotting.

RESULTS:

Exposure to CAL-101 and celecoxib significantly increased apoptosis, which was accompanied by the inactivation of AKT, Ras homolog gene family, member A (RHOA), Rho-associated coiled-coil containing protein kinase 1 (ROCK1), and ROCK2 as well as up-regulation of Phosphatase and tensin homolog (PTEN). Co-treatment with CAL-101 and celecoxib triggered the ER stress response and the down-regulation of BCL2 and BCL-XL. SB203580, SP600125, and salubrinal effectively inhibited apoptosis and attenuated expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP). Levels of apoptosis signal-regulating kinase 1 (ASK1) were also increased after treatment with CAL-101 and celecoxib.

CONCLUSION:

The apoptosis of EBV-transformed B-cells and NHL cells caused by CAL-101 and celecoxib might be related to inhibiting the RHOA/ROCK pathway and might also be associated with mitogen-activated protein kinase (MAPK)-mediated ER stress.

KEYWORDS:

CAL-101; Celecoxib; EBV-transformed B cells; ER stress

PMID:
25964548
[Indexed for MEDLINE]

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