Fibrates and medroxyprogesterone acetate induce apoptosis of primary Burkitt's lymphoma cells and cell lines: potential for applying old drugs to a new disease

Abstract

Current therapies for Burkitt's lymphoma (BL) utilise combined cytotoxic chemotherapy, but these treatments are not always available in areas where the disease is endemic and are also markedly less successful in AIDS-related BL. Therefore, additional therapies are urgently required. We demonstrate here that combined fibrates and MPA exert powerful, antiproliferative actions against well-characterised Daudi, Raji and L3055 BL cell lines and primary BL cells. Detailed studies in L3055 demonstrated that this activity was mediated by induced apoptosis and confirmed by observations that overexpression of the antiapoptotic genes bcl-2 or bcl-x L conferred significant protection against the drugs. Importantly, since fibrates and MPA are inexpensive and stable with minimal-associated toxicities, we suggest that these drugs should be considered as adjuncts to currently available treatments for BL in endemic and AIDS-related disease.

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

“…5C). Our earlier observations demonstrated that AML cell killing by BaP requires a >96-hour exposure (9), whereas killing of eBL cells is more rapid (7). Consistent with this, oleate induced a strong antiapoptotic effect in the Burkitt cell lines, as measured by decreased Annexin V staining, which was not observed in AML cells (Fig.…”

“…This approach has already been successful in reducing mortality in hematologic malignancies (5,6). Using this method, we previously identified that the combination of the lipid lowering drug, bezafibrate, and the contraceptive, medroxyprogesterone acetate (MPA), has potent and cancer cell selective in vitro anticancer effects against AML, eBL, chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphoma cells (7)(8)(9)(10). The potency of this combination (denoted BaP) extended to the clinic demonstrating efficacy with low toxicity in clinical trials in AML (trial registration number ISRCTN50635541; ref.…”

Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation

“…Acting through diverse mechanisms, these compounds usually retard or inhibit progression through the cell cycle and induce apoptosis. Examples of such compounds include fibrates and medroxyprogesterone acetate in Burkitt's lymphoma cells, 1 and psychotropics in B-cell-derived lines. 2,3 Thalidomide, an antiemetic which was withdrawn from the market in the 1960s, is thought to act by inducing cell differentiation and thereby preventing unrestrained proliferation of immature myelogenous cells.…”

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

“…BEZ is a lipid-lowering agent that mediates its activity as a ligand of the nuclear receptor PPARa and MPA is an orally active contraceptive progestogen. The study was based on our previous experience in Burkitts lymphoma 9 and acute myeloid leukemia (AML) [10][11][12] (Khanim et al, 2008, unpublished data). We show that both BEZ and MPA induce apoptosis in primary CLL cells and that the combination BEZ þ MPA is significantly more proapoptotic than either agent alone.…”