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Int J Oncol. 2017 May;50(5):1711-1720. doi: 10.3892/ijo.2017.3923. Epub 2017 Mar 21.

A p110δ-specific inhibitor combined with bortezomib blocks drug resistance properties of EBV-related B cell origin cancer cells via regulation of NF-κB.

Author information

1
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
2
Department of Anatomy, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea.
3
Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.

Abstract

Epstein-Barr virus (EBV) infection is closely related to carcinogenesis of various cancers, and is also associated with the development of drug resistance in cancer stem cells. However, in EBV-positive cancer cells, the mechanistic details of the downstream signaling and the connection of PI3K with the NF-κB pathway for development of drug resistance remain controversial. Diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) cells infected by EBV display drug resistance-related proteins (MDR1, MRP1 and MRP2) and stem cell markers (OCT4 and SOX2). EBV-infected HT (HT/EBV) and H929 (H929/EBV) cells activated p110δ expression, but downregulated the expression of p110α and p110β. A combination of CAL-101, a p110δ-specific inhibitor, with bortezomib treatment of HT/EBV cells synergistically suppressed proliferation, reduced levels of drug resistance-related proteins, activated caspase cleavage and recovered expression of p110α/p110β. Additionally, co-treatment with CAL-101 and bortezomib attenuated the expression of OCT4 and SOX2 via inhibition of activated NF-κB. Co-treatment with CAL-101 and bortezomib also attenuated drug resistance and NF-κB activity of EBV-infected H929 cells. Our results provide supportive evidence for the clinical application of CAL-101 and bortezomib to treat EBV-infected hematologic cancer.

PMID:
28339079
DOI:
10.3892/ijo.2017.3923
[Indexed for MEDLINE]

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