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Overcoming Antiapoptotic Responses to Promote Chemosensitivity in Metastatic Colorectal Cancer to the Liver

From the Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Correspondence: Address correspondence and reprint requests to: James C. Cusack, Jr., MD, Division of Surgical Oncology, Massachusetts General Hospital, 100 Blossom St., Cox 626, Boston, MA 02114; Fax: 617-724-3895; E-mail: jcusack{at}partners.org

ABSTRACT

Background: Metastatic colon cancer is highly resistant to chemotherapy. A variety of mechanisms by which cancer cells resist chemotherapy have been described including enhanced export of drug from cancer cells and alterations in drug metabolism. In addition, the response of cancer cells to genotoxic therapies may be diminished by acquired defects in either the response mechanisms to DNA damage or cell cycle regulatory pathways. Recently, attention has focused on mechanisms that are activated by treatment exposure and subsequently promote resistance by rescuing cancer cells from apoptosis. The objective of this review is to examine the role of antiapoptotic mechanisms of chemotherapy resistance and to determine the potential utility of therapeutic strategies that target these mechanisms.

Methods: To accomplish the objectives, a brief overview of mechanisms of chemotherapy resistance is provided. The concept of inducible chemotherapy resistance is introduced by examination of a specific antiapoptotic mechanism, mediated by the transcription factor, nuclear factor kappa B (NF-B). The ability to use inhibitors of NF-B to promote chemosensitivity is examined in vitro and in vivo.

Results: Inhibition of chemotherapy-induced NF-B activation enhances apoptosis and augments chemotherapy sensitivity.

Conclusions: NF-B inhibition may overcome cancer cell defense against apoptosis. Molecular therapies that target this resistance mechanism may be useful adjuncts to conventional chemotherapy.

Key Words: Chemotherapy resistance • Apoptosis • NF-B • Colon cancer • Liver metastases

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