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View the Table of Contents for the May 1 issue of Cancer Research
Krüger et al. Page 3523
Matrix metalloproteinases (MMPs), in particular gelatinases, play a key role in cancer progression. This has prompted the development of synthetic MMP inhibitors as therapeutic agents. However, clinical trials have been disappointing due to lack of specificity in inhibition. A new approach to MMP inhibition involving covalent mechanism-based inhibition has been tested by Krüger et al. in an aggressive model of experimental liver metastasis. Treatment of mice with the highly selective gelatinase inhibitor, SB-3CT, significantly reduced the growth and number of liver metastases and increased survival. This novel approach to inhibitor design brings new hopes for anti-MMP inhibitors in cancer treatment with considerable prospect for future development.
Gray et al. Page 3664
Neuropilin-1 (NRP-1) is a known co-receptor for VEGF/Semaphorin receptor family members, but its autonomous function(s) in human cancers are unclear. Gray et al. examined NRP-1 function in cells lacking NRP-1 co-receptors (VEGF-R1, -R2 and Plexin-1A) by over-expression of wild-type NRP-1 and a VEGF binding–deficient, mutant NRP-1 construct, and by reducing endogenous NRP-1 expression by siRNA. In a VEGF-independent manner, increasing NRP-1 levels decreases Akt phosphorylation, migration, and anchorage-independent growth in vitro, and tumorigenesis and tumor growth in vivo. This suggests NRP-1 has novel and distinct VEGF/Semaphorin ligand-independent functions in tissues lacking its known co-receptors and is capable of suppressing tumor formation through mechanisms which are not yet completely understood.
Pan et al. Page 3671
The antineoplastic mechanism of farnesyltransferase inhibitors (FTIs) is multi-pronged and not entirely dependent on Ras inhibition. Pan et al. demonstrated that FTIs induced reactive oxygen species (ROS) and DNA double strand breaks, and N-acetyl-L-cysteine blocked FTI-induced DNA damage. DNA repair proteins were activated. The FTI-induced oxidative DNA damage also increased RhoB. These findings link FTIs to ROS, DNA damage, DNA damage responses and RhoB in inhibiting growth and inducing apoptosis of cancer cells. This is the first report of DNA damage induced by FTIs via ROS. These data imply that inhibition of DNA repair may enhance the efficacy of FTIs.
Landowski et al. Page 3828
Calcium is a ubiquitous intracellular messenger that participates in a large number of cellular processes, including apoptosis. Using fluorescent microscopy and a spectrum of agents known to modulate Ca2+ channel activity, Landowski et al. demonstrate that proteasome inhibition induces a disregulation of intracellular Ca2+ that is mediated by the mitochondrial Ca2+ uniporter. They further demonstrated that the cytotoxic activity of the proteasome inhibitor, bortezomib (PS-341/Velcade) can be abrogated by agents that block the mitochondrial uniporter. This novel mechanism of cytotoxicity is not associated with any other chemotherapeutic agent examined, and represents a unique molecular pathway for therapeutic intervention.
El-Abaseri et al. Page 3958
Ultraviolet (UV) irradiation, the primary cause of non-melanoma skin cancer, activates the epidermal growth factor receptor (EGFR). In order to determine the biological significance of the UV-induced activation of EGFR in skin carcinogenesis, El-Abaseri et al. inhibited the receptor prior to UV exposure of v-rasHa-transgenic mice and monitored tumorigenesis. This transient inhibition of EGFR decreased tumor multiplicity and tumor size by 50% and 80%, respectively, by suppressing UV-induced cell proliferation and increasing UV-induced cell death. These results reveal the importance of EGFR activation by UV and suggest that it may be an appropriate target for intervention in skin carcinogenesis.