P 084 - Therapeutic assessment of tirapazamine-induced oxidative stress on gastric cancers

Abstract

Tirapazamine (TPZ) has been considered as a therapeutic candidate for cancers in the future. It selectively activates multiple reductases to release free radicals from hypoxic cells such as cancer cells, leading to DNA damages and cell death. This unique character of TPZ may impose less cytotoxicity on normal organs or tissue, leading to reduce the side effects on cancer patients. In this study, we conjugated TPZ onto gold nanoparticles (AuNPs) for increased stability in serum and more efficiently assessing to tumors via Enhanced Permeability and Retention (EPR) Effect. Our results demonstrated the TPZ is significantly cytotoxic to MNK45 hypoxic gastric cancer cells, but less harmful to cells growing under normoxia condition. We noticed that TPZ-induced cell death may result from oxidative stress in cells.Several detoxification enzymes such as catalase and Glutathione S-transferase P in hypoxic MNK45 cells were increased after exposure to TPZ. Moreover, our data suggested TPZ-induced cell death is mediated by apoptotic program. Furthermore, we found intravenously injected TPZ-AuNPs were largerly retained in tumors and significantly reduced the tumor volume in xenografts, suggestion TPZ-AuNP may directly impact on tumor cell proliferating and growing. Taking together, TPZ-AuNPs may be a putative candidate for cancer therapy