Picropodophyllotoxin Induces G1 Cell Cycle Arrest and Apoptosis in Human Colorectal Cancer Cells via ROS Generation and Activation of p38 MAPK Signaling Pathway

Abstract

Picropodophyllotoxin (PPT), an epimer of podophyllotoxin, is derived from the roots of Podophyllum hexandrum and exerts various biological effects, including anti-proliferation activity. However, the effect of PPT on colorectal cancer cells and the associated cellular mechanisms have not been studied. In the present study, we explored the anticancer activity of PPT and its underlying mechanisms in HCT116 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to monitor cell viability. Flow cytometry was used to evaluate cell cycle distribution, the induction of apoptosis, the level of reactive oxygen species (ROS), assess the mitochondrial membrane potential (Δψm), and multi-caspase activity. Western blot assays were performed to detect the expression of cell cycle regulatory proteins, apoptosis-related proteins, and p38 MAPK (mitogen-activated protein kinase). We found that PPT induced apoptosis, cell cycle arrest at the G1 phase, and ROS in the HCT116 cell line. In addition, PPT enhanced the phosphorylation of p38 MAPK, which regulates apoptosis and PPT-induced apoptosis. The phosphorylation of p38 MAPK was inhibited by an antioxidant agent (N-acetyl-L-cysteine, NAC) and a p38 inhibitor (SB203580). PPT induced depolarization of the mitochondrial inner membrane and caspase-dependent apoptosis, which was attenuated by exposure to Z-VAD-FMK. Overall, these data indicate that PPT induced G1 arrest and apoptosis via ROS generation and activation of the p38 MAPK signaling pathway.

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

“…99 Moreover, Lee found that PPP could also induce G1 arrest and apoptosis in human colorectal cancer cells via ROS generation and activation of the p38 MAPK signalling pathway. 100…”

Single-cell landscape and spatial transcriptomic analysis reveals macrophage infiltration and glycolytic metabolism in kidney renal clear cell carcinoma

“…AC45971100, also known as fluometuron, is an immune modulator that may exert its effects by inhibiting mitochondrial enzyme dihydroorotate dehydrogenase and effectively suppressing the growth of breast cancer cells [ 42 ]. NSC35468, or Podophyllotoxin bromide, is less commonly reported but has been suggested in literature to induce mitochondrial inner membrane depolarization and caspase-dependent apoptosis in colorectal cancer [ 43 ].…”

Melatonin controls cell proliferation and modulates mitochondrial physiology in pancreatic stellate cells

“…Our results have shown that, in the presence of melatonin, the phosphorylation of JNK and of p44/42 was diminished, whereas an increase in the phosphorylation of p38 was noted. Increased phosphorylation of p38 MAPK has been related with cell death [ 27 ]. In addition, low levels of phosphorylated JNK and p44/42 have been related with diminished cell proliferation [ 28 ].…”