Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals.
Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER) stress-induced cytotoxicity, and antioxidant activity owing to their activity as free radical scavengers, inhibition of coenzyme Q synthesis, activation of antioxidant-responsive elements (inducing detoxification enzymes) and induction of apoptosis. Activation of ER-stress responses generates reactive oxygen species (ROS), which are highly reactive free radicals mainly produced during mitochondrial electron transfer for adenosine triphosphate (ATP) synthesis. When cells are subjected to oxidative stress conditions, there is an accumulation of ROS that can lead to irreversible cell injury caused primarily by lipid peroxidation, protein aggregation and/or DNA damage. Malignant tumors, such as glioblastoma multiforme, display elevated rates of oxygen consumption, necrosis and abnormal structural microvasculature. Alterations in the tumor microenvironment are tightly linked to tumor progression and occur as a result of activation of complex signaling networks involving inter-clonal cooperation, cell-matrix interactions and an ongoing inflammatory response leading to genetic and epigenetic alterations. This review will focus on the pro- and anti-oxidant activities of POH, which are greatly dependent on the respective ROS levels within the tumor microenvironment and involve the ER stress response system. As well, some critical aspects of tumor-associated metabolic changes and the consequences of endogenous ROS production for tumor progression will be discussed.
Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, RJ, 24020-141, Brazil.
Aline C
AC
Gomes
Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, RJ, 24020-141, Brazil.
Angélica L
AL
Mello
Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, RJ, 24020-141, Brazil.
Manuel G
MG
Ribeiro
Department of Neurology, Federal University of Rio de Janeiro State, Rio de Janeiro, RJ, Brazil.
Diogo G
DG
Garcia
Department of Specialized Medicine, School of Medicine, Fluminense Federal University, Niteroi, RJ, Brazil.
Clovis O
CO
Da Fonseca
Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Marcela D'Alincourt
MD
Salazar
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
Axel H
AH
Schönthal
Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, RJ, 24020-141, Brazil. tquirico@id.uff.br.
Thereza
T
Quirico-Santos
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D063646:Carcinogenesis; D059865:Endoplasmic Reticulum Stress; D016166:Free Radical Scavengers / Q000378:metabolism* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D015227:Lipid Peroxidation; D039821:Monoterpenes / Q000378:metabolism* / Q000627:therapeutic use; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment; D056811:Unfolded Protein Response
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D039821:Monoterpenes; D017382:Reactive Oxygen Species; C032208:perillyl alcohol
Hypoxia; Perillyl alcohol; Reactive oxygen species; Tumor microenvironment