July 2007 Molecular Cancer Therapeutics Highlights

Selected Articles from the July 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 July 2007 issue of Molecular Cancer Therapeutics

PDGFRα Targets HCC

Stock et al.

Page 1932

Hepatocellular cancer (HCC) remains a disease of ominous prognosis mandating identification of novel aberrations that might have therapeutic implications. Based on commonalities between the processes of development and cancer, Stock and colleagues identified PDGFRα upregulation during liver development as well as being overexpressed in up to 70% of HCC. Based on the strategy utilized for identification, aberrant PDGFRα expression appears to be a primary mechanism in HCC. Additionally PDGF-A and C, the ligands for PDGFRα were upregulated in a subset of HCC’s also suggesting an autocrine loop in some tumors. Various human hepatoma cell lines showed varying extent of PDGFRα upregulation and activation. Treatment of these cell lines with the monoclonal antibody against PDGFRα (MAb 3G3; ImClone), showed a clear impact on tumor cell proliferation and survival. Thus, the authors identified PDGFRa as a primary and novel therapeutic target in HCC.

Notch Inhibition Induces Mitotic Catastrophe via NF-κB

Curry et al.

Page 1983

Kaposi’s sarcoma (KS) is the most common neoplasm in untreated AIDS patients, and accounts for significant morbidity and mortality worldwide. Curry and colleagues demonstrated that Notch inhibition in KS tumor cells using γ-secretase inhibitors or Notch-1 siRNA resulted in G2/M cell cycle arrest and mitotic catastrophe characterized by the presence of micronucleated cells and an increased mitotic index. Notch inhibition led to a sustained increase in nuclear cyclin B1, a novel observation suggesting that Notch signaling can modulate expression of this critical cell cycle protein. Further analysis showed the induction of cyclin B1 was due, at least in part, to increased NF-κB activity, which was also required for the G2/M growth arrest after Notch inhibition. Taken together, these studies suggested Notch inhibition can initiate aberrant mitosis by inducing NF-κB activity that inappropriately increases cyclin B1 resulting in cell death via mitotic catastrophe.

Perifosine Induces Extrinsic Apoptotic Pathway

Elrod et al.

Page 2029

Perifosine is currently in Phase II clinical trials for various types of cancer. How perifosine exerts its antitumor effects is not well understood. Elrod and colleagues show that reduction of c-FLIP expression using siRNA sensitizes tumor cells to perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP confers resistance to perifosine. Downregulation of DR5 and caspase-8 using siRNA protects cells from perifosine-induced apoptosis. Therefore, activation of the extrinsic apoptotic pathway plays a critical role in perifosine-induced apoptosis. Perifosine also cooperates with the DR5 ligand, TRAIL, to enhance apoptosis, suggesting that perifosine in combination with TRAIL may be an effective cancer treatment.

Vitamin D Enhances Radiosensitization of Prostate Cancer

Xu et al.

Page 2048

Nuclear factor κB (NF-κB) provides an adaptive response to protect cancer cells against cytotoxicity induced by redox active therapeutics. RelB is uniquely expressed at a high level in prostate cancer (PCa) with high Gleason scores. Xu and colleagues demonstrated that interaction of 1α, 25-dihydroxyvitamin D3 (1α,25-(OH)2D3) with the Vitamin D receptor (VDR) significantly enhances radiosensitivity of PCa cells at clinically relevant radiation doses. The radiosensitization effect of 1α,25-(OH)2D3 is mediated, at least in part, by selectively suppressing IR-mediated RelB activation, leading to a reduced expression of its target gene manganese superoxide dismutase (MnSOD), a primary antioxidant enzyme in mitochondria. These results suggest that suppression of MnSOD is a mechanism by which 1α,25-(OH)2D3 exerts its radiosensitization effect and that 1α,25-(OH)2D3 may serve as an effective pharmacologic agent for selectively sensitizing PCa cells to IR via suppression of antioxidant responses in mitochondria.

July 2007 Molecular Cancer Therapeutics Highlights

Selected Articles from the July 1, 2007 Issue

PDGFRα Targets HCC

Notch Inhibition Induces Mitotic Catastrophe via NF-κB

Perifosine Induces Extrinsic Apoptotic Pathway

Vitamin D Enhances Radiosensitization of Prostate Cancer

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