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Is Bcl-2 protein a major obstacle in treating colorectal carcinoma?

September 24, 2008

Apoptosis resistance has been shown to contribute to the development of different cancer entities, such as colorectal carcinoma (CRC). Moreover, apoptosis resistance of carcinoma cells provides an explanation for low response rates in patients with advanced cancer receiving chemotherapy. Thus, new treatment options to sensitize carcinoma cells to apoptosis induction are needed. It has been previously shown that anti-apoptotic Bcl-2 proteins, such as Bcl-xL and Mcl-1, are expressed in CRC. These proteins inhibit apoptosis induction by interacting with pro-apoptotic Bcl-2 proteins, thereby blocking the activation of mitochondria. Since mitochondria are central organelles in apoptotic signal pathways, activation of mitochondria is an approach to sensitize CRC cells to apoptosis induction. In patients suffering from CRC, new anti-cancer agents have proven to improve survival rates. Further modern approaches target death receptors expressed on CRC cells, such as the death receptor TRAIL-R1 and -R2. So far, it is not known, if the modulation of anti-apoptotic Bcl-2 proteins influences the apoptosis sensitivity of CRC cells towards modern therapy approaches.

A research article to be published on 28 June 2008, in World Journal of Gastroenterology addresses this question.

The research team leaded by Dr. Henning Schulze-Bergkamen from the First Medical Department of the University of Mainz, showed that expression of the anti-apoptotic Bcl-2 family protein Bcl-xL is higher in CRC tissue compared to surrounding non-malignant tissues. For the anti-apoptotic Bcl-2 family protein Mcl-1, a slightly higher expression in malignant tissue was observed. Knock down of Bcl-xL expression in CRC cells via a mechanism called RNA interference, induced cell death in CRC cells. In addition, knock down of Bcl-xL sensitized CRC cells to cell death induction caused by chemotherapy (oxaliplatin, irinotecan, 5-FU), blockage of the EGFR receptor (cetuximab, PD168393) and death receptor ligands (CD95L, TRAIL). Furthermore, knock down of Mcl-1 sensitized CRC cells to irinotecan, oxaliplatin and EGFR blockage.

Apoptosis resistance is a major obstacle for the treatment of patients with advanced CRC. These data show that anti-apoptotic Bcl-2 proteins, such as Bcl-xL and Mcl-1, are important anti-apoptotic factors in CRC. In patients suffering from CRC, chemotherapy and targeted therapy approaches (like EGFR blockage or triggering of the death receptor TRAIL-R) are likely to be improved by adding agents which inhibit the expression of Bcl-xL and Mcl-1.

World Journal of Gastroenterology