American Association for Cancer Research

February 2008 Molecular Cancer Therapeutics Highlights

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Selected Articles from the February 1, 2008 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Molecular Cancer Therapeutics is published. Click on the article title to view the complete article.

View the Table of Contents for the February 2008 issue of Molecular Cancer Therapeutics


TRPV6 Influences Breast Cancer Cell Proliferation

Bolanz et al.

Page 271

TRPV6 is a calcium entry channel that is strongly expressed in breast adenocarcinoma tissue. In this study Bolanz and colleagues further confirmed this observation by analysis of breast cancer tissues, which indicated that TRPV6 mRNA expression was upregulated between 2- and 15-fold compared to the average in normal breast tissue. Their in vitro model demonstrated that TRPV6 can be regulated by estrogen, progesterone, tamoxifen, and 1,25-vitamin D and has a large influence on breast cancer cell proliferation. Moreover, the effect of tamoxifen on cell viability was enhanced when TRPV6 expression was silenced with siRNA. TRPV6 may be a novel target for the development of calcium channel inhibitors to treat breast adenocarcinoma expressing TRPV6. 


MKP-1 Inactivated by a Small Molecule

Vogt et al.

Page 330

Studies suggest induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) during chemotherapy may limit the efficacy of clinically used antineoplastic agents. Thus MKP-1 is a rational target to enhance anticancer drug activity, but suitable small molecule inhibitors of MKP-1 are currently unavailable. Vogt and colleagues used a high-content, multiparameter fluorescence-based chemical complementation assay for MKP activity in intact mammalian cells to evaluate the cellular MKP-1 and MKP-3 inhibitory activities of four previously described, quinone-based dual specificity phosphatase inhibitors. All compounds induced formation of reactive oxygen species in mammalian cells, but only one (NSC 95397) inhibited cellular MKP-1 and MKP-3 with an IC50 value of 13 µM. 


IKKβ Inhibitor Induces Cell Death in BCR-ABL+ Cells

Duncan et al.

Page 391

Inhibition of BCR-ABL kinase activity with imatinib has led to dramatic success in treatment of patients with CML. However, resistance to imatinib, and to newer drugs such as dasatinib, occurs through point mutations in ABL. These findings suggest that inhibition of key downstream signaling molecules could function as an additional therapy for patients with BCR-ABL+ malignancies. The NF-κB pathway was previously shown to be induced by BCR-ABL and to be required for tumor formation in a xenograft model.  Duncan and colleagues showed that inhibition of IKKβ, an upstream regulator of NF-κB-dependent signaling, induced potent cytotoxic/growth-inhibitory responses in BaF/3 and 32D cells expressing wild-type or drug resistant variants of BCR-ABL. 


Among children with refractory neuroblastoma novel strategies are needed to improve survival. High vascular density within neuroblastoma is associated with advanced disease. Beaudry and colleagues carried out dual targeting of neuroblastoma tumor cells and tumor endothelium with ZD6474, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) and RET. ZD6474 inhibited the phosphorylation of RET in neuroblastoma cells and decreased the viability of neuroblastoma cell lines. In xenografts, ZD6474 potently inhibited tumor growth. Immunohistochemical analysis demonstrated that ZD6474 treatment led to inhibition of VEGFR2 signaling and marked endothelial cell apoptosis. Dual targeting of tumor cells and vasculature may improve outcomes. 


Optical Imaging Probe Monitors

Peng et al.

Page 432

Due to the lack of high-affinity targeting ligands, molecular imaging of α4β1 integrin is much less explored than that of integrins αvβ3 and αvβ5. Peng and colleagues described the use of LLP2A-Cy5.5 conjugate as an in vivo optical imaging probe in a human lymphoma xenograft model. This univalent LLP2A-Cy5.5 conjugate retained the binding activity and specificity to α4β1 integrin as shown by cell binding assays using α4β1-positive Molt-4 T-leukemia cells. This study demonstrated that the combinatorial chemical library-derived peptidomimetic LLP2A can be easily developed into an optical imaging probe for noninvasively monitoring of activated α4β1 integrin in vivo.


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