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

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.

Reference: Schulze-Bergkamen H, Ehrenberg R, Hickmann L, Vick B, Urbanik T, Schimanski CC, Berger MR, Schad A, Weber A, Heeger S, Galle PR, Moehler M. Bcl-xL and Mcl-1 contribute to apoptosis resistance of colorectal cancer cells. World J Gastroenterol 2008; 14(24): 3829-3840
http://www.wjgnet.com/1007-9327/14/3829.asp

Correspondence to: Henning Schulze-Bergkamen, MD, PhD, First Department of Medicine, Johannes-Gutenberg-University Mainz, Langenbeckstraße 1, Mainz 55101, Germany. bergkam@uni-mainz.de
Telephone: +49-6131-172462 Fax: +49-6131-175529

World Journal of Gastroenterology (WJG), a leading international journal in gastroenterology and hepatology, has established a reputation for publishing first class research on esophageal cancer, gastric cancer, liver cancer, viral hepatitis, colorectal cancer, and H pylori infection and provides a forum for both clinicians and scientists. WJG has been indexed and abstracted in Current Contents/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch) and Journal Citation Reports/Science Edition, Index Medicus, MEDLINE and PubMed, Chemical Abstracts, EMBASE/Excerpta Medica, Abstracts Journals, Nature Clinical Practice Gastroenterology and Hepatology, CAB Abstracts and Global Health. ISI JCR 2003-2000 IF: 3.318, 2.532, 1.445 and 0.993. WJG is a weekly journal published by WJG Press. The publication dates are the 7th, 14th, 21st, and 28th day of every month. WJG is supported by The National Natural Science Foundation of China, No. 30224801 and No. 30424812, and was founded with the name of China National Journal of New Gastroenterology on October 1, 1995, and renamed WJG on January 25, 1998.

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