Betulinic acid, a natural cytotoxic agent, fails to trigger apoptosis in human Burkitt's lymphoma‐derived B‐cell lines

Abstract

Betulinic acid (BA), a pentacyclic triterpene of natural origin, effectively induces apoptosis in neuroectodermal tumors and was recently shown to be a potent trigger of cell death in human leukemia-derived cell lines. To explore the potential of BA in the treatment of hematologic malignancies, we tested a panel of 10 Burkitt's lymphoma (BL)-derived B-cell lines for sensitivity to BA. The human Jurkat T leukemia cell line was included as a positive control. Our studies show that BA exerts cytotoxic effects in some of the BL cell lines tested, including DG75, a chemoresistant BL cell line. However, cell death was caspase-independent, as evidenced by a lack of protection by zVAD-fmk, a pancaspase inhibitor, and displayed signs of necrosis. Furthermore, BA-induced caspase activation was seen to a minor extent in only 1 of the 10 BL cell lines tested (Ramos, a p53-deficient cell line), but was readily detected in Jurkat cells. Together, these studies indicate that resistance to BA-induced apoptosis is a common feature of BLderived cell lines. ' 2005 Wiley-Liss, Inc.

Requirement of Apoptotic Protease-Activating Factor-1 for Bortezomib-Induced Apoptosis but Not for Fas-Mediated Apoptosis in Human Leukemic Cells

“…For flow cytometric assessment of DNA content and cell cycle distribution (Karpova et al, 2006), cells were harvested and resuspended in a solution containing PI (50 mg/ml), 0.1% Triton X-100, and 0.1% sodium citrate in PBS. Cells were then analyzed on a FACScan (Becton Dickinson) operating with CellQuest software (Becton Dickinson).…”

(2α,3β)‐2,3‐Dihydroxyolean‐12‐en‐28‐oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells

“…Moreover, their beneficial effects have been analysed by extensive preclinical and epidemiological studies [1][2][3][4]. Some natural triterpenoids such as oleanolic, betulinic and ursolic acids have shown notable effects in suppressing tumourigenesis as well as inhibiting tumours [1,[5][6][7][8][9]. Also, a range of newly developed synthetic triterpenoids are more potent than the naturally occurring parent structure [10,11].…”

Smac-mediated sensitization of human B-lymphoma cells to staurosporine- and lactacystin-triggered apoptosis is apoptosome-dependent

“…Briefly, cells were harvested, washed and resuspended in a HEPES buffer containing annexin V-FITC and propidium iodide (PI) (100 mg/ml) before analysis on a FACScan (Becton Dickinson), as described previously. 10 Cellular uptake of FITC-conjugated Smac and control peptides (see section above) was also assessed using a FACScan operating with CellQuest software (Becton Dickinson).…”

“…To verify that the importance of Apaf-1 for apoptosis signaling is not limited to the Raji cell line, we utilized DG-75-lymphoma cells, that are resistant to the chemotherapeutic agent, etoposide, 10,11 as well as to STS (the present study). Our previous studies have shown that the lipid raft-disrupting agent, methylb-cyclodextrin (MCD), can sensitize both the Raji cell line and the DG-75 cell line to cytochrome c-dependent activation of caspases, through the liberation of endogenous Apaf-1 from the plasma membrane.…”

“…6 Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin's lymphoma characterized at the molecular genetic level by chromosomal rearrangements of the c-myc oncogene. 7 We and others have shown that BL-derived B cell lines frequently are resistant to apoptosis, [8][9][10] and we have recently provided evidence that ectopic, noncytosolic localization of Apaf-1 may function as a novel mechanism of chemoresistance in these cells. 11 Enforced expression of exogenous Apaf-1 or disruption of lipid raft domains with subsequent liberation of endogenous Apaf-1 rendered these cells chemosensitive.…”