Avermectin Confers Its Cytotoxic Effects by Inducing DNA Damage and Mitochondria-Associated Apoptosis

Abstract

Avermectin (AVM) has been widely used in agriculture and animal husbandry on the basis of its broad spectrum of effective anthelmintic activity and specificity targets. However, AVM induction of cytotoxicity through DNA damage is remains elusive. Here we investigate the cytotoxic effects of AVM in human nontarget cells in vitro. We clarify that AVM inhibited the viability of HeLa cells and enhanced apoptosis. We have used alkaline comet assay and γH2AX foci formation to detect DNA damage of HeLa cells. As expected, we found AVM caused DNA double-strand breaks in HeLa cells, as measured by significance of comet assay parameters (e.g., tail DNA) and increases of γH2AX foci in HeLa cells. Moreover, established assays of cytotoxicity were performed to characterize the mechanism of AVM toxicity on HeLa cells. The results demonstrated the collapse of mitochondrial membrane potential, and up-regulating the expression level of Bax/Bcl-2 resulted in a release of cytochrome c into cytosol as well as the activation of caspase-9/-3 and cleavage of poly(ADP-ribose) polymerase (PARP). We conclude that AVM has a potential risk to human health by inducing human cell DNA damage and mitochondria-associated apoptosis.

Fengycins, Cyclic Lipopeptides from Marine Bacillus subtilis Strains, Kill the Plant-Pathogenic Fungus Magnaporthe grisea by Inducing Reactive Oxygen Species Production and Chromatin Condensation

“…The DNA repair enzyme poly(ADP-ribose) polymerase (PARP) can be activated by DNA strand breaks, and its cleavage is an important indication of cell death (43, 50). In this study, the Western blot analyses showed that in the control group, most PARP proteins were full length with a molecular weight approximately 68 kDa, and only a few PARP proteins were cleaved (Fig.…”

“…grisea hyphal cells (Fig. 5), which might lead to the release of mitochondrial intermembrane proteins into the cytoplasm, triggering cellular fragmentation and DNA damage and eventually causing cell apoptosis (24, 50). Collectively, the induction of ROS bursts by fengycin BS155 is suggested to contribute to cell death in M.…”

Abamectin induces apoptosis and autophagy by inhibiting reactive oxygen species‐mediated PI3K/AKT signaling in MGC803 cells

“…Moreover, ABA can induce apoptosis in King pigeon brain neurons and pigeon liver and inhibit the goat liver carbonic anhydrase enzyme . In vitro bioassays, ABA induces HeLa and HepG2 cell DNA damage and apoptosis …”

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

“…21 Apoptosis mainly occurs through two pathways: the intracellular pathway (mitochondrial-mediated), the two principal features of which are collapse of the mitochondrial membrane potential (ΔΨm) and the release of cytochrome c, and the extracellular pathway (death receptor-mediated). 22 AVM stimulates the release of cytochrome c into the cytosol in HeLa cells. Moreover, the effector caspase-3 and the initiating agent caspase-9 are both activated, and this activation induces the cleavage of poly ADP-ribose polymerase (PARP), which is a substrate of caspase-3 and a fundamental component of apoptosis.…”

“…Both of these caspases associated with apoptosis are augmented by AVM, and the repair and healing of AVMinduced DNA damage are simultaneously blocked. 22 Similarly, the treatment of breast cancer cells with ivermectin induces the cleavage of PARP, caspase-1 activity, which is characteristic of pyroptotic cell death, and the activation of caspase-3, which typically occurs in classic apoptosis. 23 Studies have shown that Z-VAD-FMK, a pan-caspase inhibitor, eliminates the pro-apoptotic influence of ivermectin on K562, U87, NBM CD34, CML and T98G cells, which indicates that ivermectin induces apoptosis in glioblastoma and chronic myeloid leukaemia cells through a caspasedependent pathway.…”