Superoxide dismutase as a target for the selective killing of cancer cells

Huang, Peng; Li, Feng; Oldham, E. A.; Keating, Michael J.; Plunkett, William

doi:10.1038/35030140

Cited by 769 publications

(619 citation statements)

References 22 publications

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“…Inhibition of SOD-1 by TR could decrease the capacity of endothelial cells to scavenge the increased level of superoxides, resulting in growth arrest, apoptosis, and inhibition of angiogenesis. These data are in good agreement with recent findings demonstrating that another SOD-1 inhibitor (Huang et al, 2000) -2-methoxyoestradiol is also anti-angiogenic (Fotsis et al, 1994). No damage was observed in already established (non-proliferating) blood vessels in the treated animals.…”

Section: Discussionsupporting

confidence: 93%

“…Since angiogenesis is characterised by proliferating endothelial cells and reoxygenation, we speculated that inhibition of SOD-1 will diminish the ability of endothelial cells to confront the increased level of ROS during angiogenesis, thus, resulting in inhibition of angiogenesis, of tumour development and metastasis. This assumption is consistent with recent findings demonstrating that the anti-angiogenic compound 2-methoxyoestradiol (Fotsis et al, 1994) is a SOD-1 inhibitor (Huang et al, 2000).…”

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confidence: 93%

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Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

Marikovsky

2002

Br J Cancer

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Thiram-tetramethylthiuram disulphide -a chelator of heavy metals, inhibited DNA synthesis and induced apoptosis in cultured bovine capillary endothelial cells. Bovine capillary endothelial cells were 10 -60-fold more sensitive to thiram than other cell types. These effects were prevented by addition of antioxidants, indicating involvement of reactive oxygen species. Exogenously added Cu 2+ impeded specifically and almost completely the inhibitory effect of thiram for bovine capillary endothelial cells. Moreover, thiram had markedly inhibited human recombinant Cu/Zn superoxide dismutase enzymatic activity (85%) in vitro. Moreover, PC12-SOD cells with elevated Cu/Zn superoxide dismutase were less sensitive to thiram treatment than control cells. These data indicate that the effects of thiram are mediated by inhibition of Cu/Zn superoxide dismutase activity. Oral administration of thiram (13 -30 mg mouse 71 ), inhibited angiogenesis in CD1 nude mice. Tumour development is known to largely depend on angiogenesis. We found that oral administration of thiram (30 mg) to mice caused significant inhibition of C6 glioma tumour development (60%) and marked reduction (by 3 -5-fold) in metastatic growth of Lewis lung carcinoma. The data establish thiram as a potential inhibitor of angiogenesis and raise the possibility for its use as therapy in pathologies in which neovascularisation is involved, including neoplasia.

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Section: Discussionsupporting

confidence: 93%

supporting

confidence: 93%

Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

Marikovsky

2002

Br J Cancer

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“…A mitochondria-dependent mechanism was demonstrated in leukemia, pancreatic carcinoma, Ewing sarcoma and multiple myeloma cells. 19,27,37,41 On the other hand, the use of the FIGURE 3 -Effect of 2ME 2 on the microtubular organization in HT168-M1 human melanoma cells. Cells were cultured on coverslips and treated with Taxol (100 nM, 10 min) or 2ME 2 (5 M, 1 hr).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

Dobos

Tı́már

Bocsi

et al. 2004

Intl Journal of Cancer

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2-methoxyestradiol (2ME 2 ) is an endogenous metabolite of estradiol with estrogen-receptor-independent antitumor and antiangiogenic activity. We examined the effects of 2ME 2 on the cellular proliferation of 8 human melanoma cell lines. We show that 2ME 2 inhibited cell proliferation by inducing apoptosis and an arrest in the G 2 /M phase, and the mechanism of action involved microtubules, mitochondrial damage and caspase activation. In male SCID mice, 2ME 2 was effective in reducing primary tumor weight and the number of liver metastases after intrasplenic injection of human melanoma cells. In the metastases, we found a significantly higher rate of apoptotic cells after 2ME 2 treatment. These findings on the antitumor effect of 2ME 2 in cell culture as well as in an animal model may have implications for designing alternative treatment options for patients with advanced malignant melanoma. © 2004 Wiley-Liss, Inc. Key words: 2-methoxyestradiol; melanoma; apoptosis; metastasisThe possibility that endocrine factors may influence the clinical course of human malignant melanoma is suggested by the higher survival rate in premenopausal vs. postmenopausal women or men of any ages. 1,2 The epidemiological data were supported by studies using melanoma cell lines grown in experimental animals. 3,4 Our previous experiments showed that intrasplenic injection of human melanoma cells resulted in a significantly higher number of liver metastases in male than in female SCID mice. 5 On the other hand, investigations on the sex hormone receptor status of human cutaneous melanomas yielded conflicting results; while earlier studies applying biochemical methods for the detection of estrogen receptors (ER) gave positive results in some cases, other approaches using monoclonal anti-ER antibodies generally failed to demonstrate the presence of type I receptors in melanoma tissues. 1,6 It has been suggested that low-affinity type II ERs may be responsible for the observed hormone binding. Nevertheless, most investigators have shown the lack of an effect of estrogens on the proliferative activity of human melanoma cells. 7,8 There are less data available on the presence of other sex hormone receptors (progesterone and androgens) and their effect on the biological behavior of melanoma cells. 1,9 One possible mechanism behind the observed female superiority in survival of melanoma patients is the tumor growth inhibitory effect of 2-methoxyestradiol (2ME 2 ), an endogenous metabolite of estradiol exerting its activities independently of the ERs. 2ME 2 is formed by the sequential hydroxylation and methylation at the 2-position; it is produced during the normal route of detoxification, especially in the liver, and excreted through the urinary system. 10 -12 This is the only estradiol metabolite devoid of estrogenic activity in vivo and has no known physiological function. Its affinity to ER␣ and to ER␤ is 500-fold and 3,200-fold lower than that of estradiol, respectively, and its activity is independent of the presence of estrogen receptor...

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“…antisense or chemical inhibitors) targeting cyclin E/CDK (Sausville et al, 2000) or SOD activities (Huang et al, 2000) could also be tested as chemosensitising tools to anthracycline treatment in cyclin E-overexpressing tumours.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of cyclin E is associated with an increased resistance to doxorubicin in rat fibroblasts

et al. 2003

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Cell cycle progression in eukaryotic cells is regulated by a family of cyclin-dependent kinases (CDKs). Cyclin E is a regulatory subunit of CDK2 and drives cells from G1 to S phase. Increased expression of cyclin E is a frequent event in human malignancies and has been associated with poor prognosis in various cancers. In this study, we evaluated the effects of cyclin E-overexpression on the sensitivity of rat fibroblasts to anticancer drugs. Cyclin E-overexpressing cells were less sensitive to doxorubicin-induced inhibition of cell growth but not to other antineoplastic drugs, such as paclitaxel, vincristine, etoposide and methotrexate. Cyclin E-overexpressing fibroblasts also displayed a reduction in ROS levels and a significantly lower increase following doxorubicin treatment compared with vector control cells. The expression of manganese superoxide dismutase (MnSOD) and its activity were increased (about 1.3-fold) in cyclin E-overexpressing derivatives compared with control cells. These results suggest that cyclin E overexpression might reduce tumour cells sensitivity to doxorubicin by affecting the expression of MnSOD and that determination of cyclin E expression levels might help to select patients to be treated with an anthracycline-based antineoplastic therapy.

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Superoxide dismutase as a target for the selective killing of cancer cells

Cited by 769 publications

References 22 publications

Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

In vitro and in vivo antitumor effect of 2‐methoxyestradiol on human melanoma

Increased expression of cyclin E is associated with an increased resistance to doxorubicin in rat fibroblasts

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