Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells

Abstract

The synthetic curcumin analogue, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24), suppresses NF-κB activity and exhibits antiproliferative effects against a variety of cancer cells in vitro. Recently, it was reported that EF-24-induced apoptosis was mediated by a redox-dependent mechanism. Here, we studied the effects of N-acetylcysteine (NAC) on EF-24-induced cell death. We also addressed the question of whether the main drug transporters, ABCB1 and ABCG2, affect the cytotoxic of EF-24. We observed that EF-24 induced cell death with apoptotic hallmarks in human leukemia K562 cells. Importantly, the loss of cell viability was preceded by production of reactive oxygen species (ROS), and by a decrease of reduced glutathione (GSH). However, neither ROS production nor the decrease in GSH predominantly contributed to the EF-24-induced cell death. We found that EF-24 formed an adduct with GSH, which is likely the mechanism contributing to the decrease of GSH. Although NAC abrogated ROS production, decreased GSH and prevented cell death, its protective effect was mainly due to a rapid conversion of intra- and extra-cellular EF-24 into the EF-24-NAC adduct without cytotoxic effects. Furthermore, we found that neither overexpression of ABCB1 nor ABCG2 reduced the antiproliferative effects of EF-24. In conclusion, a redox-dependent-mediated mechanism only marginally contributes to the EF-24-induced apoptosis in K562 cells. The main mechanism of NAC protection against EF-24-induced apoptosis is conversion of cytotoxic EF-24 into the noncytotoxic EF-24-NAC adduct. Neither ABCB1 nor ABCG2 mediated resistance to EF-24.

Bioactivities of EF24, a Novel Curcumin Analog: A Review

“…Accumulating evidence suggests EF24 to be active in cell and/or tumor models of numerous cancer types. For example, in in-vitro experiments, it is effective in inhibiting osteogenic sarcoma cells (31), malignant pleural mesothelioma cells (32), progressive medullary thyroid cancer cells (33), human pancreatic cancer cells (34) and leukemia/lymphoma cells (20, 35). Whether used alone or in combination with other agents, EF24 displays great potential as an anti-cancer therapeutic.…”

“…Therefore, it seems that the role of EF24 in ROS induction may be cell type-dependent, and more evidence is needed to clarify these contradictory results. Interestingly, Skoupa et al recently concluded that apoptosis induced by the EF-24 is not mediated by oxidative stress-related in human leukemia cells (20). A redox-dependent-mediated mechanism only marginally contributes to the EF24-induced apoptosis in K562 cells.…”

“…The authors reported that EF24 induced cell cycle arrest and apoptosis via a redox-dependent mechanism in cancer cells (19). Later, EF24 was shown to have promising bioactivities, especially its anti-cancer activity in various solid tumors (18) and leukemia (20). Compared to the classical chemotherapy drug cisplatin, EF24 is more efficacious and less toxic (18).…”

Anti-Cancer and Ototoxicity Characteristics of the Curcuminoids, CLEFMA and EF24, in Combination with Cisplatin

“…CLEFMA causes death in lung cancer cells via ROS production and activation of multiple apoptotic effector molecules [19,20,21,22]. EF24 also kills cancer cells by signaling through multiple apoptotic mechanisms, but the role of ROS production in EF24-mediated cell death is uncertain [23,24,25]. Although cisplatin, CLEFMA, and EF24 affect similar components in apoptotic signaling pathways, dissimilarities between cisplatin and these curcuminoids have been identified, including their effect on glutathione signaling, which is implicated in cisplatin-resistance [1,19,24].…”

Acute Myeloid Leukaemia: New Targets and Therapies

“…Apoptosis can also be induced in human leukaemia cells by the curcumin analogue EF-24. In their study, Skoupa and colleagues [ 17 ] investigate the mechanism by which EF-24 induces cell death in K562 cells. They propose that EF-24 may be suitable as an anticancer agent, specifically in cases of drug resistance.…”