American Association for Cancer Research

December 2007 MCT Highlights

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Selected Articles from the December 1, 2007 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 December 2007 issue of Molecular Cancer Therapeutics


SFK Inhibition Enhances RA-Induced Differentiation in AML

Miranda et al.

Page 3081

Differentiation therapies hold considerable promise for the treatment of acute myeloid leukemias (AMLs). In acute promyelocytic leukemia (APL), induction of differentiation with retinoic acid (RA) is curative. However, other forms of AML do not respond to RA, and the cellular factors that regulate responsiveness to RA are largely unknown. Miranda and colleagues discovered that Src family kinases (SFKs) act as negative regulators of RA-induced gene expression and differentiation. Inhibition of SFKs markedly enhanced RA-induced differentiation of myeloid cell lines and primary, nonAPL, AML cells. Thus, inhibition of SFKs, in combination with RA, may have therapeutic benefit in AML. 
 

Flavopiridol and Vorinostat Interaction Lethal in Breast Cancer Cells

Mitchell et al.

Page 3101

The drug combination of flavopiridol and vorinostat are entering phase I trials in hematologic and solid tumor malignancies. Although studies have been published regarding how these agents interact in blood cancers, relatively little is known how these agents interact in transformed epithelial cells (or in transformed cells attached to a substratum). The studies by Mitchell and investigators determined that concurrent treatment of breast cancer cells with clinically relevant concentrations of the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza™) resulted in a synergistic level of cell killing in vitro. However, prior treatment of cells with vorinostat suppressed the toxicity of the drug interaction.


CDDO-Me is a Potent Anti-angiogenic Agent

Vannini et al.

Page 3139

The concept of angioprevention, chemoprevention directed at inhibition of tumor angiogenesis, is now an important component in this overall preventive approach. For effective angioprevention, new molecules are needed to inhibit vascular promotion of tumor growth in vivo. Vannini and investigators showed that the synthetic oleanane triterpenoid, CDDO-Methyl Ester (CDDO-Me, methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate), is an effective agent for suppressing angiogenesis, both in cell culture and in vivo. However, the particularly potent anti-angiogenic activity seen in vivo in these experiments suggested that CDDO-Me may be interacting with an entire network of molecular and cellular targets, rather than at a single molecular locus or in a single cell type.


TRAIL, a TNF superfamily member, targets death receptors and selectively kills malignant cells while leaving normal cells unaffected. However, unlike most cancers, many osteosarcomas are resistant to TRAIL. Locklin and colleagues investigated this resistance using TRAIL and agonist antibodies to the death receptors DR4 and DR5 and found that MG-63 osteosarcoma cells carry a dominant-negative mutation which can confer TRAIL resistance. However an agonist antibody to the active death receptor was able to induce apoptosis in these resistant cells. Thus treatment with an appropriate receptor agonist can override cellular defences and could provide a tailored approach to treat resistant osteosarcomas. 


Vitamin K3 Transported by ABCG2

Shukla et al.

Page 3279

The multidrug resistance-linked ABCG2 transporter plays an important role in the body by acting as a barrier to limit the oral bioavailability of the drugs and also protects cells by transporting toxic compounds out of the cells. Shukla and colleagues found that the naphthoquinones, vitamin K3 (also called menadione) and its structural analog plumbagin are substrates of this transporter and these compounds at low micromolar concentrations inhibit the ABCG2-mediated efflux of anticancer substrates. This study identified menadione as a physiological substrate of ABCG2 and further suggests potential use of menadione and its analogs to increase the efficacy of chemotherapy in cancer patients.