Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

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Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

Reactive oxygen species (ROS) stimulate cell proliferation and induce genetic instability, and their increase in cancer cells is often viewed as an adverse event. Here, we show that such abnormal increases in ROS can be exploited to selectively kill cancer cells using beta-phenylethyl isothiocyanate (PEITC). Oncogenic transformation of ovarian epithelial cells with H-Ras(V12) or expression of Bcr-Abl in hematopoietic cells causes elevated ROS generation and renders the malignant cells highly sensitive to PEITC, which effectively disables the glutathione antioxidant system and causes severe ROS accumulation preferentially in the transformed cells due to their active ROS output. Excessive ROS causes oxidative mitochondrial damage, inactivation of redox-sensitive molecules, and massive cell death. In vivo, PEITC exhibits therapeutic activity and prolongs animal survival.

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The Period2 gene plays a key role in controlling circadian rhythm in mice. We report here that mice deficient in the mPer2 gene are cancer prone. After gamma radiation, these mice show a marked increase in tumor development and reduced apoptosis in thymocytes. The core circadian genes are induced by gamma radiation in wild-type mice but not in mPer2 mutant mice. Temporal expression of genes involved in cell cycle regulation and tumor suppression, such as Cyclin D1, Cyclin A, Mdm-2, and Gadd45alpha, is deregulated in mPer2 mutant mice. In particular, the transcription of c-myc is controlled directly by circadian regulators and is deregulated in the mPer2 mutant. Our studies suggest that the mPer2 gene functions in tumor suppression by regulating DNA damage-responsive pathways.

Superoxide dismutases (SOD) are essential enzymes that eliminate superoxide radical (O2-) and thus protect cells from damage induced by free radicals. The active O2- production and low SOD activity in cancer cells may render the malignant cells highly dependent on SOD for survival and sensitive to inhibition of SOD. Here we report that certain oestrogen derivatives selectively kill human leukaemia cells but not normal lymphocytes. Using complementary DNA microarray and biochemical approaches, we identify SOD as a target of this drug action and show that chemical modifications at the 2-carbon (2-OH, 2-OCH3) of the derivatives are essential for SOD inhibition and for apoptosis induction. Inhibition of SOD causes accumulation of cellular O2- and leads to free-radical-mediated damage to mitochondrial membranes, the release of cytochrome c from mitochondria and apoptosis of the cancer cells. Our results indicate that targeting SOD may be a promising approach to the selective killing of cancer cells, and that mechanism-based combinations of SOD inhibitors with free-radical-producing agents may have clinical applications.