Oxidative Stress: A Double Edged Sword in Cancer

Abstract

Production of free radicals and reactive oxygen species (ROS) inside the cell causes cellular oxidative stress. Superoxides, hydroxyl radicals, nitric oxides, hydrogen peroxide, and singlet oxygen radicals are some of the examples of ROS exhibiting their involvement in cancer. The slight increase in cellular ROS favors the development of a tumor, and a very high level of intracellular ROS increases oxidative stress to induce death of cancer cells. Hence, the role of intracellular ROS signaling in promoting cancer cell proliferation, angiogenesis, and metastasis on one side and very high ROS-induced oxidative stress leading to autophagy and cell death on the other end acts as a double-edged sword in cancer. Tetrandrine, a potent bioactive bisbenzylisoquinoline alkaloid, has been reported as an antioxidant agent to reduce diabetic and inflammatory conditions. However, tetrandrine is known to induce mitochondrial damage, resulting in increased membrane potential and release of ROS in cancer cells, which leads to autophagy, cell cycle arrest, and apoptosis. Studies have shown the tetrandrine-induced increased intracellular ROS and up−/downregulation of different signaling molecules, such as ERK, Akt, mTOR, Ulk, Beclin-1, LC3, and Atg to induce macroautophagy or mitophagy in different cancers. Also, up−/downregulation of JNK, Bcl-2 family anti- and proapoptotic proteins, caspases, cyclins, and cyclin-dependent kinase (CDK) regulators of the cell cycle was detected in tetrandrine-treated cancer cells favoring cell DNA damage, cell cycle arrest, and apoptosis. Hence, tetrandrine could be a strong candidate for the development of an anticancer drug.KeywordsTetrandrineROSAutophagyApoptosisCell cycle arrestIntrinsic caspase pathwayExtrinsic caspase pathwayLC3Beclin