2009 AACR Annual Meeting
April 18-22, 2009
Denver, CO
Abstract Number: 8

Source

Session Title: Biological and Biochemical Mechanisms of Prevention
Presentation Title:

A translational research paradigm by using pharmacological agents that will mimic or couple with dietary energy restriction for breast cancer prevention

Presentation Start/End Time: Sunday, Apr 19, 2009, 8:00 AM -12:00 PM
Location: Hall B-F, Poster Section 1
Poster Section: 1
Poster Board Number: 8
Author Block: Zongjian Zhu, Weiqin Jiang, John N. McGinley, Elizabeth S. Neil, Jennifer L. Sells, Denise K. Rush, Henry J. Thompson. Colorado State University, Ft. Collins, CO, Colorado State University, Fort Collins, CO

Emerging evidence from studies of human populations indicates that excessive energy intake is associated with an increased risk for cancer, but that dietary energy restriction (DER) is protective. Similarly, DER has been shown to be a potent inhibitor of carcinogenesis in most of the experimental models in which it has been investigated. However, current trends in the prevalence of overweight and obesity suggest that simply recommending limits to daily energy intake will be neither feasible nor attractive to most individuals as a cancer prevention strategy. It was for this reason that in our current work we decided to determine if it is possible to identify drugs that mimic the cancer preventive activity of DER in the absence of limiting energy intake.

The objective of these experiments was to test two hypotheses: 1) that induction of the activity of AMP-activated protein kinase by metformin would inhibit mammary carcinogenesis and 2) that blocking the switch to aerobic glycolysis observed in cancers (the Warburg effect) by treatment with an dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, would block mammary tumor development.

Female Sprague Dawley rats (n=30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter randomized to control, metformin, or dichloroacetate (DCA) dietary groups and fed respective diets for 5 weeks.

Both metformin and DCA significantly reduced the number of mammary adenocarcinoma per rat (p<0.05). The mechanisms implicated include down regulation of mTOR activity by metformin and increased activity of pyruvate dehydrogenase by DCA.

Supported by PHS grant CA52626 from the National Cancer Institute.