Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7

Abstract

Verrucarin A (VA), an active constituent of pathogenic fungus Myrothecium verrucaria, which has the ability to inhibit the growth of breast cancer cells. However, the mechanism by which VA exerts its inhibitory potential remains elusive. Here, we demonstrated that VA inhibited the growth of MCF-7 breast cancer cells, increased the levels of reactive oxygen species (ROS), and subsequently induced mitochondrial membrane potential (Δψm) loss, leading to the increase of Bax/Bcl-2 ratio, cytochrome c release, caspase activation, PARP degradation, and apoptosis. VA effectively increased the phosphorylation of p38MAPK and diminished the phosphorylation of ERK/Akt. In addition, VA caused cell cycle deregulation through the induction of p21 and p53. Furthermore, ROS scavenger (n-acetyl-L-cysteine) and p38MAPK inhibitor (SB202190) effectively abrogated the VA-induced cell cycle deregulation and apoptosis. Conversely, U0126, an ERK1/2 inhibitor, enhanced the VA-induced apoptotic signals. Taken together, our results suggest that VA-induces apoptosis and cell cycle deregulation in MCF-7 cells through ROS-dependent p38MAPK activation.

The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-κB/mTOR prosurvival signaling

“…The antiproliferative effect of VC-A was attributed to the inhibition of cell cycle progression in S phase. This finding however differs from a previous report in which VC-A was shown to arrest cells in G0/G1 phase (17). Furthermore, cell cycle arrest by VC-A was associated with the inhibition of cyclin D1, cyclin E, cdk2, cdk-4 and cdk inhibitor p21.…”

“…Indeed, isolation and identification of bioactive components from medicinal plants have led to the synthesis of potent anticancer drugs, including Vinca alkaloids, taxol, camptothecan, etoposide and retinoids. Verrucarin A (VC-A) is a macrocyclic trichothecene mycotoxin that has shown strong antiproliferative and proapoptotic activity in breast cancer cells (17,18), providing some insights into the mode of action of VC-A. However, the antitumor activity or the mechanism of action of VC-A in pancreatic cancer cells has not been investigated.…”

“…They elicit a wide range of biological responses in eukaryotic cells, including inhibition of protein synthesis and cell proliferation; induction of cytotoxicity, ribotoxic stress responses and modulation of immune responses (11)(12)(13)(14)(15)(16). Verrucarin A (VC-A) is a macrocyclic trichothecene that evokes strong antiproliferative and proapoptotic responses in cancer cells (17)(18)(19)(20). There is some evidence that the antiproliferative and apoptosis-inducing effects of VC-A are due to the inhibition of protein synthesis through blocking of peptidyl transferase activity and activation of c-jun N-terminal kinase (c-JNK) and p-38 MAP kinase (14,17,18).…”

“…Verrucarin A (VC-A) is a macrocyclic trichothecene that evokes strong antiproliferative and proapoptotic responses in cancer cells (17)(18)(19)(20). There is some evidence that the antiproliferative and apoptosis-inducing effects of VC-A are due to the inhibition of protein synthesis through blocking of peptidyl transferase activity and activation of c-jun N-terminal kinase (c-JNK) and p-38 MAP kinase (14,17,18).…”

Downregulation of TRIM27 expression inhibits the proliferation of ovarian cancer cells in vitro and in vivo

“…It has been reported that the p38MAPK pathway could participate in a variety of physiological and pathological processes, including cell proliferation, cell cycle regulation and cell apoptosis. 22,23 Palanivel et al 24 found that Verrucarin A (VA) induces apoptosis and cell cycle deregulation in MCF-7 cells through ROS-dependent p38MAPK activation. Kim et al 25 also reported that the activation of the p38MAPK pathway induced Bax phosphorylation and mitochondrial translocation and apoptosis of HepG2 cells.…”