One of the main challenges in cancer therapy is the excessive toxicity of chemotherapeutics due to their nonselective activity. One strategy to preferentially target cancer cells is to utilize agents that preferentially kill cells lacking p53.We have recently identified a plant-derived alkaloid that has seen clinical use primarily for neurological disorders that can preferentially induce death in colon cancer cells in the absence of p53. This compound induces cell death in p53-null cells by inducing the expression of a p53 family member, p73, which activates apoptosis. Interestingly, in the presence of p53, p73 is not induced by this alkaloid and cells undergo a p53- dependent cell cycle arrest that protects them from apoptosis. In this proposal we aim to assess 1) the unique regulation of p73 by this natural compound 2) mechanisms through which this agent induces apoptosis and 3) the clinical potential of this agent for colon cancer using mouse xenograft studies. Not only will this proposal provide biological insights into novel mechanisms that modulate p73 but it may also lead to a new use of an existing therapeutic agent for colon cancer therapy.

Public Health Relevance

Most existing chemotherapeutic agents suffer from excessive toxicities. The development and understanding of novel agents that exhibit more selectivity in killing cancer cells is highly desirable. These studies aim to assess the clinical potential and mechanisms of a plant derived product that is able to preferentially target colon cancer cells.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AT006536-03
Application #
8651428
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Duffy, Linda C
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106