A new study describes in detail exactly how the chemotherapeutic drug paclitaxel induces cell death in tumor cells and how common mutations in human tumors confer drug resistance, and demonstrates that combination treatment can restore therapeutic effectiveness of the drug. The research is published in the March issue of the journal Cancer Cell.

When damaged or stressed, normal cells die via a carefully controlled process called apoptosis. In contrast, cancer cells keep dividing, often due to genetic errors that disrupt the mechanisms required to induce apoptosis. Dr. Eileen White from Rutgers University and colleagues examined the role of a molecule called BIM in tumorigenesis and chemotherapeutic response to paclitaxel, a drug that has been used successfully to treat breast, prostate, ovarian, and lung cancers. The researchers examined BIM because it has been implicated as a tumor suppressor and is known to play a role in the regulation of apoptosis.

The researchers found that BIM accumulation is absolutely required for paclitaxel-induced apoptosis, and that BIM deficiency is associated with paclitaxel-resistant tumors. Further research revealed that the H-ras/MAPK signaling pathway suppresses paclitaxel-mediated BIM induction by causing BIM to be targeted for destruction in proteosomes, thereby blocking the ability of BIM to induce apoptosis. Importantly, cotreatment with paclitaxel and a proteosome inhibitor currently approved for use in clinical trials restored paclitaxel-stimulated BIM accumulation and apoptosis that enabled tumor regression.

The H-ras/MAPK pathway is intimately linked to promotion of cell survival and is often abnormally activated during tumorigenesis. The researchers conclude that combinatorial chemotherapy using proteosome inhibitors to enhance chemosensitivity to paclitaxel in tumors where the H-ras/MAPK pathway is activated may be therapeutically beneficial.

These results suggest that a clear underst
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Contact: Heidi Hardman
hhardman@cell.com
1-617-397-2879
Cell Press
14-Mar-2005

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