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. 2012 Apr;103(4):775-81.
doi: 10.1111/j.1349-7006.2012.02212.x. Epub 2012 Feb 21.

Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF-κB pathway

Hiroki Goto  1 , Ryusho Kariya, Masako Shimamoto, Eriko Kudo, Manabu Taura, Harutaka Katano, Seiji Okada
Affiliations

Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF-κB pathway

Hiroki Goto et al. Cancer Sci. 2012 Apr.

Abstract

Primary effusion lymphoma (PEL) is an infrequent and distinct entity among the aggressive non-Hodgkin B cell lymphomas that occurs predominantly in patients with advanced AIDS. It shows serous lymphomatous effusion in body cavities, and is resistant to conventional chemotherapy with a poor prognosis. Thus, the optimal treatment for PEL is not well defined and there is a need for novel agents. PEL has been recognized as the tumor caused by Kaposi sarcoma-associated herpes virus/human herpes virus-8 (KSHV/HHV-8), and nuclear factor (NF)-κB activation plays a critical role in the survival and growth of PEL cells. In this study, we assessed the antitumor effect of berberine, a naturally occurring isoquinoline alkaloid, on this pathway. The methylthiotetrazole assay showed that cell proliferation in the PEL cell lines was inhibited by berberine. Berberine also induced caspase-dependent apoptosis and suppressed NF-κB activity by inhibiting IκB kinase (IKK) phosphorylation, IκB phosphorylation and IκB degradation, upstream targets of the NF-κB pathway, in PEL cells. In a xenograft mouse model that showed ascites and diffuse organ invasion of PEL cells, treatment with berberine inhibited the growth and invasion of PEL cells significantly compared with untreated mice. These results show that the suppression of NF-κB is a molecular target for treating PEL, and berberine is a potential antitumor agent for PEL.

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Figures

Figure 1
Figure 1
Chemical structure of berberine chloride.
Figure 2
Figure 2
Berberine inhibits the proliferation of primary effusion lymphoma (PEL) cells. PEL cell lines (BC‐1, BCBL‐1 and TY‐1) and non‐PEL cell line (U937) were incubated with 0, 3, 10, 30, 10 and 100 μM berberine for 24 h. A cell proliferation assay was carried out using MTT as described in the Materials and MethodsMaterials and Methods. One representative result from three independent experiments is shown.
Figure 3
Figure 3
Berberine induces apoptosis in BCBL‐1 cells. (a) Berberine‐induced apoptosis was detected by Annexin V staining. A primary effusion lymphoma cell line, BCBL‐1, was treated with berberine (30, 100 μM) for 24 h and was subsequently stained with Annexin V‐Alexa fluor 647 before being analyzed by flow cytometry. (b) Berberine caused DNA fragmentation of nuclei. BCBL‐1 cells were treated with berberine (30, 100 μM) for 48 h. (c) BCBL‐1 cells were treated with 100 μM berberine for 0, 1, 3 and 6 h and total proteins were extracted for western blotting.
Figure 4
Figure 4
Inhibitory effects of berberine on the expression of NF‐κB pathways. (a) A primary effusion lymphoma cell line, BCBL‐1, was treated with 100 μM berberine for 0, 1, 3 and 6 h and total proteins were extracted for western blotting. (b) BCBL‐1 cells were treated with 100 μM berberine for 0, 1, 3 and 6 h and nuclear proteins were extracted for western blotting to detect NF‐κB p65. (c) BCBL‐1 cells were treated with 100 μM berberine for 0, 12, 24 and 48 h and assessed for NF‐κB DNA binding activity by EMSA using an NF‐κB‐specific oligonucleotide probe.
Figure 5
Figure 5
Treatment of NOD/Rag‐2/Jak‐3‐deficient mice with berberine suppresses the development of PEL in vivo. (a) Photograph of berberine‐treated and untreated ascites‐bearing mice 4 weeks after inoculation with BCBL‐1 i.p. (b) The body weight of mice 4 weeks after inoculation with BCBL‐1 cells in berberine‐treated or untreated mice is shown as the mean ± SD of 6 mice. (c) The volume of ascites 4 weeks after inoculation with BCBL‐1 cells in mice is shown as the mean ± SD of 6 mice. (d) Overall survival curve. Treatment with berberine prolongs survival in vivo.
Figure 6
Figure 6
Invasion of primary effusion lymphoma cells into the organs of BCBL‐1‐inoculated mice on day 28. (a) Hematoxylin–eosin (HE) staining and immunohistochemical staining using anti‐LANA (PA1‐73N antibody) was performed to detect BCBL‐1 in the liver, lung and spleen. (b) Viral gene expression after treatment with berberine. Viral gene expression in spleen of berberine treated and untreated mouse was examined by RT‐PCR. A representative result from two experiments is shown.
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