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.

Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

Oxidative Stress, Inflammation, and Cancer: How Are They Linked?

The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.

Modulation of oxidative stress as an anticancer strategy.

Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.

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Reactive oxygen species in cancer

http://basicmed.med.ncku.edu.tw/admin/up_img/981030-3.pdf

Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening

The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

Association of reactive oxygen species levels and radioresistance in cancer stem cells

Background:Over the years, the prognosis following treatment of a primary cancer has significantly improved. However, the growing population of these cancer survivors has led to the realization of multiple longterm complications secondary to their treatment. One of the most devastating long-term complications is the development of a second malignancy. CaseReports:We report here the case of a 34-year-old man who developed stage IIB node-positive breast cancer almost 15 years following total body irradiation and allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia. To our knowledge, this is only the second report of a male breast cancer following allogeneic bone marrow transplantation (BMT). Conclusion:Survivors of primary cancer need lifelong monitoring for complications from their initial therapy.

Male breast cancer 15 years after allogeneic hematopoietic cell transplantation including total body irradiation for recurrent acute lymphoblastic leukemia.

3515 Background: Complete pathologic response (CR) following neoadjuvant chemotherapy (NCT) is achieved in only a third of patients, although the CR rate doubles in those with HER2 over-expressing (+) tumors. Therefore, more efficient regimens as well as better predictors of outcome are needed. Objectives: To assess the feasibility and efficacy (defined by CR rate) of a novel regimen in comparison to standard therapy in the neoadjuvant setting; to assess the feasibility of sequential tissue procurement and to identify molecular predictors of CR with emphasis on markers of receptor/signal transduction pathways and their feedback loops. Methods: Patients with stages II-III HER- breast cancer are randomized on a prospective phase II trial to receive 6 cycles of docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 (TAC, arm A) versus doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 given every 2 weeks x 4, followed by 3 weekly doses of carboplatin (AUC 2) and paclitaxel albumin-bound 100 mg/m2 given every 4 weeks x 3 cycles (ACAC; arm B). A separate stratum of patients with HER2 + tumors are included in this trial and they receive ACAC and 12 weekly doses of trastuzumab given during the administration of carboplatin and paclitaxel albumin-bound (ACAC-T, arm C). Core biopsies of the untreated primary breast tumor are performed prior to treatment and mid-therapy, and tumor is also procured at completion from the definitive surgical specimens. Fresh frozen, formalin-fixed paraffin-embedded, and ethanol preserved tumor and adjacent stromal tissues are procured for extraction of RNA and protein analysis, allowing assessment of protein and gene expression patterns. The immunohistochemically targeted proteins include ER, PR, HER2, EGFR, p-Stat3, p-AKT, p-Src, Survivin, p21, p27, Ki67. Results: Twenty seven patients received at least one cycle of therapy (41 were screened, but due to upstaging or other eigilibility problems only 30 have or are about to receive treatment). For the 27 patients median age is 50 years (range-31-69); 13 patients presented with stage II and 14 with stage III disease (6 patients were enrolled with inflammatory breast cancer); 29% of tumors are HER2 +. Pre-treatment biopsies were successfully procured from all, and 70% of study-required mid-treatment biopsies were performed. So far, no study-limiting toxicities have been observed on either arm: grade 4 hematologic toxicities were seen on arm A (n:5); B (n:4); and C:(n:4 cases). There were no grade 2 or greater neurotoxicities. All 5 evaluable patients treated on Arm C were found to have either CR (n:3), or minimal microscopic residual disease. Conclusion: The study design is feasible, and the novel regimen is active. Scheduled comparative analysis of toxicities, CR rate, and assessment of biological markers in the first 35 patients who will have undergone definitive surgery will be presented.

Jeannie Shen

Papers

Association of reactive oxygen species levels and radioresistance in cancer stem cells

Male breast cancer 15 years after allogeneic hematopoietic cell transplantation including total body irradiation for recurrent acute lymphoblastic leukemia.

A randomized phase II neoadjuvant trial in patients with stages II-III and inflammatory breast cancer.