Plumbagin enhances TRAIL-induced apoptosis of human leukemic Kasumi-1 cells through upregulation of TRAIL death receptor expression, activation of caspase-8 and inhibition of cFLIP

Abstract

Abstract. Although the patients with t(8;21) acute myeloid leukemia (AML) have a favorable prognosis compared with other non-acute promyelocytic leukemia AML patients, only ~50% patients with this relatively favorable subtype can survive for 5 years and refractory/relapse is common in clinical practice. So it is necessary to find novel agents to treat this type of AML. In this study, the effects and the mechanisms of plumbagin and recombinant soluble tumor necrosis factor-α-related apoptosis-inducing ligand (rsTRAIL) on leukemic Kasumi-1 cells were primarily investigated. Plumbagin and/or rsTRAIL could significantly inhibit the growth of Kasumi-1 cells and induce apoptosis in vitro and in vivo. Plumbagin enhanced TRAIL-induced apoptosis of Kasumi-1 cells in association with mitochondria damage, caspase activation, upregulation of death receptors (DRs) and decreased cFLIP expression. The effects of plumbagin on the expression of DR5, Bax and cFLIP could be partially abolished by the reactive oxygen species (ROS) scavenger NAC. Glutathione (GSH) depletion by plumbagin increased the production of ROS. In vivo, there was no obvious toxic pathologic change in the heart, liver and kidney tissues in any of the groups. Comparing with the control mice, a significantly increased number of apoptotic cells were observed in the combined treated mice by flow cytometry. Plumbagin also increased the expression of DR4 and DR5 in cells of xenograft tumors. Collectively, our results suggest that both plumbagin and rsTRAIL could be used as a single agent or synergistical agents to induce apoptosis of leukemic Kasumi-1 cells in vitro and in vivo.

Antiproliferation for Breast Cancer Cells by Ethyl Acetate Extract of Nepenthes thorellii x (ventricosa x maxima)

“…Plumbagin is a common naphthoquinone in Nepenthes, however, isoplumbagin but not plumbagin is identified in EANT. Plumbagin was reported to bind to GSH [28], behave as electrophile against GSH [29], and induce GSH depletion of leukemia Kasumi-1 [30] and U937 [31] cells. However, the GSH effect of isoplumbagin remains unclear.…”

Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP

“…As TRAIL-mediated apoptosis is mediated through the activation of the caspase cascade ( 15 ), whether caspase-8 and caspase-3 expression was increased in GBC-SD cells treated with TRAIL or CR-31 alone was next determined. The results showed that the levels of pro-caspase-8 were weakly decreased when treated with CR-31 or TRAIL alone, along with an increase in cleaved-caspase-8 expression ( Fig.…”

Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics

“…Table 1 shows the naphthoquinone derivatives that have been reported to have anti-AML activity. Mono- or di-substituted monomeric naphthoquinones, including menadione [19], juglone [20], lawson [21], glycinyl-1,4-naphthoquinone [22], plumbagin [23,24,25,26,27], lapachol (and nor-lapachol) [21,28,29], atovaquone [30,31], ramentaceone [32], cordiaquinone J [33], and TW-92 [34] showed anti-AML activity in different AML cell lines and primary cells from AML patients with wide IC 50 s ranging from 0.6 to 100 micromolar (μM), Table 1. Atovaquone was found to have an additive effect when combined with standard induction chemotherapy (cytarabine and daunorubicin) in AML cell lines [31].…”