Selective induction of apoptosis by capsaicin in transformed cells: the role of reactive oxygen species and calcium

Abstract

Capsaicin is a vanilloid quinone analog that inhibits the plasma membrane electron transport (PMOR) system and induces apoptosis in transformed cells. Using a cytofluorimetric approach we have determined that capsaicin induces a rapid increase of reactive oxygen species (ROS) followed by a subsequent disruption of the transmembrane mitochondrial potential (DC m ) and DNA nuclear loss in transformed cell lines and in mitogen activated human T cells. This apoptotic pathway is biochemically different from the typical one induced by either ceramide or edelfosine where, in our system, the DC m dissipation precedes the generation of reactive oxygen species. Neither production of ROS nor apoptosis was found in capsaicin-treated resting T cells where the activity of the PMOR system is minimal when compared with mitogen activated or transformed T cells. Capsaicin also induces Ca 2+ mobilization in activated but not in resting T cells. However, preincubation of cells with BAPTA-AM, which chelate cytosolic free calcium, did not prevent ROS generation or apoptosis induced by capsaicin, suggesting that ROS generation in capsaicin treated cells is not a consequence of calcium signaling and that the apoptotic pathway may be separated from the one that mobilizes calcium. Moreover, we present data for the implication of a possible vanilloid receptor in calcium mobilization, but not in ROS generation. These results provide evidence that the PMOR system may be an interesting target to design antitumoral and anti-inflammatory drugs.

Anandamide Induces Apoptosis in Human Cells via Vanilloid Receptors

“…Upstream activation of the arachidonate cascade leads to redox unbalance and organelle disruption, which both favor cytochrome c release, then caspases act as downstream executioners of the death program. In this context, it seems noteworthy that also capsaicin-induced PCD occurs through intracellular calcium rise, imbalance of the redox level, and drop in mitochondrial membrane potential (43), further strengthening the hypothesis that AEA is acting through vanilloid receptors. Scheme I summarizes the series of events responsible for AEA-induced cell death.…”

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

“…To test our assumption, we sought to determine whether buffering the level of [Ca 2ϩ ] c with a cell permeant Ca 2ϩ chelator could inhibit CDDO-induced apoptosis. We pretreated COLO 16 cells with BAPTA acetoxymethyl ester, a cell-permeant agent that is hydrolyzed in the cytoplasm to yield the Ca 2ϩ chelator BAPTA (29), to determine whether we could buffer the increase in [Ca 2ϩ ] c caused by CDDO treatment. As illustrated in Fig.…”

Derivatives of monoglycerides as apoptotic agents in T-cells

“…41,42 For instance, it has been shown that the disruption of calcium homeostasis can trigger apoptosis, 56 that some apoptotic pathways lead to an increase in the concentration of intracellular calcium, 57 and that calcium chelators inhibit cell death in some systems, 58 but not all. 34,59,60 We observed that MGs induce a sustained elevation of intracellular calcium which implicates both a flux from extracellular source as well as mobilization of intracellular stores (Figure 2). Of interest are the distinct kinetics and intensity in intracellular calcium rises seen with the different MGs.…”

“…61 Nevertheless, while derivatives of MGs induce a calcium flux, they do not appear, under the conditions tested, to be essential for cell death induction, as also shown with other apoptotic experimental systems. 34,59,60,62 The exact mechanism by which MGs induce apoptosis is currently unknown. It is conceivable that MGs could simply induce cell death through a non-specific effect.…”