Piperlongumine inhibits proliferation and survival of Burkitt lymphoma in vitro

Abstract

Piperlongumine (PL), a pepper plant alkaloid from Piper longum, kills solid tumor cells in a highly selective, potent fashion. To evaluate whether PL may have similar effects on malignant blood cells, we determined the efficacy with which PL inhibits the B-lymphocyte derived neoplasm, Burkitt lymphoma (BL). Low micromolar concentrations of PL (IC50 = 2.8 × 8.5 μM) curbed growth and survival of two EBV+ BL cell lines (Daudi, Raji) and two EBV− BL cell lines (Ramos, DG-75), but left normal peripheral blood B-lymphocytes unharmed. PL-dependent cytotoxicity was effected in part by reduced NF-κB and MYC activity, with the former being caused by inhibition of IκBα degradation, nuclear translocation of p65, and binding of NF-κB dimers to cognate DNA sequences in gene promoters. In 4 of 4 BL cell lines, the NF-κB/MYC-regulated cellular target genes, E2F1 and MYB, were down regulated, while the stress sensor gene, GADD45B, was up regulated. The EBV-encoded oncogene, LMP-1, was suppressed in Daudi and Raji cells. Considering that NF-κB, MYC and LMP-1 play a crucial role in the biology of many blood cancers including BL, our results provide a strong preclinical rationale for considering PL in new intervention approaches for patients with hematologic malignancies.

Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB–Regulated Gene Products

“…These results are in agreement with recent reports that piperlongumine can suppress LPS-induced NF-kB activation in endothelial cells (9) and PMA-induced NF-kB activation in murine macrophages (36). Our results are also consistent with another recent report that piperlongumine inhibits constitutive NF-kB expression in Burkitt lymphoma cells (14).…”

“…The compound has also been shown to inhibit the enzymatic activity of GST p 1 and carbonyl reductases and to decrease glutathione levels, indicating that piperlongumine-mediated apoptosis of cancer cells is induced by a reactive oxygen species (ROS)-dependent mechanism (18). In addition, piperlongumine-dependent cytotoxicity may involve suppression of NF-kB, MYC, and LMP-1 in Burkitt lymphoma (14). Piperlongumine was shown to inhibit NF-kB activity in prostate cancer cells recently (23); however, the underlying mechanism is unclear.…”

“…Piperlongumine has multiple pharmacologic activities: it has been described as a platelet aggregation inhibitor (3), an anxiolytic agent (4), an antidepressant (5), an antinociceptive agent (6), an anti-atherosclerotic agent (7), an antidiabetic agent (8), an anti-inflammatory agent (9), and an infectious pathogen inhibitor (10). Furthermore, piperlongumine has been reported to kill multiple types of cancer cells, inhibit metastasis, and have antitumor activities in a variety of animal models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…How piperlongumine acts as an anticancer agent is not yet clear. Several studies have demonstrated that it induces cytotoxicity through a variety of mechanisms, such as activation of caspases (14,20,21), activation of the ERK pathway (11), inhibition of cdc-2, cdk2, and cyclin D1 (19, B, dose-dependent effect of piperlongumine on TNFa-induced NF-kB activation. KBM-5 cells were treated with the indicated concentrations of piperlongumine for 4 hours and then exposed to 0.1 nmol/L TNFa for 30 minutes.…”

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

“…Among the multivalent effects, the potential of piperlongumine as a novel anticancer agent have gained considerable attention recently. Emerging evidence suggests that piperlongumine is capable of killing multiple types of cancer cells, including Burkitt lymphoma (25), head and neck cancer (26), ovarian cancer (27), glioblastoma multiforme (28), breast cancer (29), prostate cancer (30), and colon cancer (31). This alkaloid was also found to sensitize tumors to chemotherapeutic agents such as cisplatin and paclitaxel (26,27).…”