Generation of Reactive Oxygen Species by Polyenylpyrroles Derivatives Causes DNA Damage Leading to G2/M Arrest and Apoptosis in Human Oral Squamous Cell Carcinoma Cells

Abstract

Oral squamous cell carcinoma (OSCC) accounts for 5.8% of all malignancies in Taiwan and the incidence of OSCC is on the rise. OSCC is also a common malignancy worldwide and the five-year survival rate remains poor. Therefore, new and effective treatments are needed to control OSCC. In the present study we have investigated the efficacy and associated mechanisms of polyenylpyrroles and their analogs in both in vitro cell culture and in vivo nude mice xenografts. Auxarconjugatin B (compound 1a) resulted in cell cycle arrest in the G2/M phase and caspase-dependent apoptosis in OEC-M1 and HSC-3 cells by activating DNA damage and mitochondria dysfunction through the loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein level, and decrease in B-cell lymphoma-2 level. Compound 1a-induced generation of intracellular reactive oxygen species through cytochrome P450 1A1 was identified as a major mechanism of its effect for DNA damage, mitochondria dysfunction and apoptosis, which was reversed by antioxidant N-acetylcysteine as well as cytochrome P450 1A1 inhibitor and specific siRNA. Furthermore, compound 1a-treated nude mice showed a reduction in the OEC-M1 xenograft tumor growth and an increase in the caspase-3 activation in xenograft tissue. These results provide promising insights as to how compound 1a mediates cytotoxicity and may prove to be a molecular rationale for its translation into a potential therapeutic against OSCC.

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

“…This finding is consistent with a previous report on another PI3K/ mTOR inhibitor, BEZ235 (13). Combining the dual PI3K/mTOR inhibitor and IR induced an elevated level of DNA damage, and this could explain the G 2 -M arrest because G 2 -M phase arrest is a hallmark of DNA damage (39). Furthermore, the level of cyclin D1, which is a vital protein, required for the G 1 -S transition, was decreased 24 hours after treatment with GSK2126458 or PKI-587, supporting the observations on cell-cycle changes.…”

Sinularin induces oxidative stress‐mediated G2/M arrest and apoptosis in oral cancer cells

“…However, this proliferation problem can be partly solved by activating checkpoints for drug‐induced cell cycle arrest . For example, several drugs had been reported to induce G2/M arrest by ROS signaling for inhibiting cancer cell proliferation, such as erianin in osteosarcoma, asperlin in cervical carcinoma, physalin A in lung cancer cells, and polyenylpyrroles derivatives in oral cancer cells . Similarly, we found the sinularin induced ROS generation and G2/M arrest leading to apoptosis in oral cancer cells.…”

Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways

“…ROS production induced by AR-42 was only partially reversed by the ROS scavenger NAC ( Fig 2A ), indicating that AR-42 also induced other sources of ROS ( e . g ., iNOS, or xanthine oxidase), which caused DNA damage or cell death [ 38 , 39 ]. However, AR-42 did not induce ROS in acute myelogenous leukemia [ 5 ], suggesting that upregulation of ROS production by AR-42 might be a tumor type-specific phenomenon.…”